U.S. patent number 8,563,606 [Application Number 13/153,427] was granted by the patent office on 2013-10-22 for solid forms of selective androgen receptor modulators.
This patent grant is currently assigned to GTx, Inc.. The grantee listed for this patent is Tai Ahn, Thomas G. Bird, James T. Dalton, David A. Dickason, Seoung-Soo Hong. Invention is credited to Tai Ahn, Thomas G. Bird, James T. Dalton, David A. Dickason, Seoung-Soo Hong.
United States Patent |
8,563,606 |
Dalton , et al. |
October 22, 2013 |
Solid forms of selective androgen receptor modulators
Abstract
The present invention relates to solid forms of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and process for producing the same.
Inventors: |
Dalton; James T. (Lakeland,
TN), Dickason; David A. (Cordova, TN), Hong;
Seoung-Soo (Collierville, TN), Bird; Thomas G. (Eads,
TN), Ahn; Tai (Lakeland, TN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Dalton; James T.
Dickason; David A.
Hong; Seoung-Soo
Bird; Thomas G.
Ahn; Tai |
Lakeland
Cordova
Collierville
Eads
Lakeland |
TN
TN
TN
TN
TN |
US
US
US
US
US |
|
|
Assignee: |
GTx, Inc. (Memphis,
TN)
|
Family
ID: |
41569205 |
Appl.
No.: |
13/153,427 |
Filed: |
June 5, 2011 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20110263703 A1 |
Oct 27, 2011 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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12228100 |
Sep 29, 2008 |
7968603 |
|
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12209137 |
Sep 11, 2008 |
7977386 |
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60960012 |
Sep 11, 2007 |
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Current U.S.
Class: |
514/522;
558/414 |
Current CPC
Class: |
A61P
5/00 (20180101); C07C 253/30 (20130101); A61P
5/26 (20180101); A61K 31/277 (20130101); C07C
255/60 (20130101) |
Current International
Class: |
A61K
31/277 (20060101); C07C 255/51 (20060101); A61P
5/00 (20060101) |
Field of
Search: |
;514/522 ;558/414 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Matsumoto, "Hormonal Therapy of Male Hypogonal", Endocrinol. Met.
Clin. N. Am. 23:857-75 (1994). cited by applicant .
Zhou, et al., "Specificity of Ligand-Dependent Androgen Receptor
Domain Interactions Influence Ligand dissociation and Receptor
Stability", Molec. Endocrinol. 9:208-18 (1995). cited by applicant
.
Sundaram et al., "7 Alpha-Methyl-Nortestosterone(MENT): The Optimal
Androgen for Male Contraception," Ann. Med., 25:199-205 (1993).
cited by applicant .
Langer, "New Methods of Drug Delivery", Science 249:1527-1533
(1990). cited by applicant .
Treat et al., "Liposome Encapsulated Doxorubicin in Preliminary
Results of Phase I and Phase II Trials", in Liposomes in the
Therapy of Infectious Disease and Cancer, Lopez-Berestein and
Fidler (eds.), Liss, New York, pp. 353-365 (1989). cited by
applicant .
Lopez-Berestein, "Treatment of Systemic Fungal Infections with
Liposomal-Amphotericin B", in Liposomes in the Therapy of
Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.),
Liss, New York, pp. 317-327 (1989). cited by applicant.
|
Primary Examiner: Chu; Yong
Attorney, Agent or Firm: Pearl Cohen Zedek Latzer Baratz LLP
Cohen; Mark S.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This Application is a divisional application of U.S. application
Ser. No. 12/228,100, filed on Sep. 29, 2008, now U.S. Pat. No.
7,968,603,which is a continuation in part of U.S. application Ser.
No. 12/209,137, filed on Sep. 11, 2008, now U.S. Pat. No.
7,977,386, which claims the benefit of U.S. Provisional Application
Ser. No. 60/960,012, filed on Sep. 11, 2007, which are incorporated
in their entirety herein by reference.
Claims
What is claimed is:
1. A paracrystalline form of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound whereby said paracrystalline form is
paracrystalline form B'' characterized by: a. an X-ray powder
diffraction pattern produced using a tube anode of Cu with Ka
radiation, said diffraction pattern displaying a broad halo with
two harmonic peaks between 15-25.degree.2.theta. and b. a phase
transition point of about 55.degree. C. as determined by
differential scanning calorimetry (DSC).
2. A composition comprising the paracrystalline form B'' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide of claim 1 and a suitable carrier or diluent.
3. A process for the preparation of a paracrystalline form B'' of
compound
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-h-
ydroxy-2-methylpropanamide according to claim 1 comprising
evaporation of said compound from ethanol without an
antisolvent.
4. A process for the preparation of a paracrystalline form B'' of
compound
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-h-
ydroxy-2-methylpropanamide according to claim 1 comprising melting
or heating a solid form A of said compound to 80.degree. C.
followed by cooling, wherein the solid form A of said compound is
characterized by: a) an X-Ray Powder diffraction pattern comprising
peaks at .degree.2.theta. (d value .ANG.) angles of about 5.6
(15.9), 7.5 (11.8), 8.6 (10.3), 9.9 (8.9), 12.4 (7.1), 15.0 (5.9),
16.7 (5.3), 17.3 (5.1), 18.0 (4.9), 18.5 (4.8), 19.3 (4.6), 19.8
(4.5), 20.6 (4.3), 21.8 (4.1), 22.3 (4.0), 23.4 (3.8), 23.9 (3.7),
24.6 (3.6), 24.9 (3.6), 25.4 (3.5), 26.0 (3.4), 26.5 (3.4), 27.8
(3.2); and b) a melting point of about 80.degree. C.
5. A process for the preparation of a paracrystalline form B'' of
compound
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-h-
ydroxy-2-methylpropanamide according to claim 1 comprising melting
or heating a solid form D of said compound to 130.degree. C.
followed by cooling, wherein the solid form D of said compound D is
characterized by: a) an X-Ray Powder diffraction pattern comprising
unique peaks at .degree.2.theta. (d value .ANG.) angles of about
4.4 (19.9), 8.5 (10.4), 8.8 (10.0), 11.3 (7.8), 12.7 (6.9), 13.8
(6.4), 14.4 (6.1), 14.6 (6.0), 15.1 (5.8), 16.1 (5.5), 16.6 (5.3),
16.9 (5.2), 18.0 (4.9), 18.7 (4.7), 19.0 (4.6), 19.4 (4.55), 20.8
(4.25), 22.1 (4.0), 22.7 (3.9), 23.1 (3.8), 23.4 (3.8), 24.7 (3.6),
24.9 (3.56), 25.3 (3.51), 27.8 (3.2), 29.3 (3.0); and b) a melting
point of about 130.degree. C.
6. The paracrystalline form of claim 1, wherein said
paracrystalline form B'' is a thermotropic liquid crystalline
form.
7. A composition comprising a mixture of crystalline and
paracrystalline solid form B'' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound of claim 1 and a suitable carrier or
diluent.
Description
FIELD OF INVENTION
The present invention relates to solid forms of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and processes of preparation thereof.
BACKGROUND OF THE INVENTION
The androgen receptor ("AR") is a ligand-activated transcriptional
regulatory protein that mediates induction of male sexual
development and function through its activity with endogenous
androgens. Androgens are generally known as the male sex hormones.
The androgenic hormones are steroids which are produced in the body
by the testes and the cortex of the adrenal gland or can be
synthesized in the laboratory. Androgenic steroids play an
important role in many physiologic processes, including the
development and maintenance of male sexual characteristics such as
muscle and bone mass, prostate growth, spermatogenesis, and the
male hair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am.
23:857-75 (1994)). The endogenous steroidal androgens include
testosterone and dihydrotestosterone ("DHT"). Testosterone is the
principal steroid secreted by the testes and is the primary
circulating androgen found in the plasma of males. Testosterone is
converted to DHT by the enzyme 5 alpha-reductase in many peripheral
tissues. DHT is thus thought to serve as the intracellular mediator
for most androgen actions (Zhou, et al., Molec. Endocrinol.
9:208-18 (1995)). Other steroidal androgens include esters of
testosterone, such as the cypionate, propionate, phenylpropionate,
cyclopentylpropionate, isocarporate, enanthate, and decanoate
esters, and other synthetic androgens such as
7-Methyl-Nortestosterone ("MENT`) and its acetate ester (Sundaram
et al., "7 Alpha-Methyl-Nortestosterone (MENT): The Optimal
Androgen For Male Contraception," Ann. Med., 25:199-205 (1993)
("Sundaram"). Because the AR is involved in male sexual development
and function, the AR is a likely target for effecting male
contraception or other forms of hormone replacement therapy.
New innovative approaches are urgently needed at both the basic
science and clinical levels to develop compounds which are useful
for a) male contraception; b) treatment of a variety of
hormone-related conditions, for example conditions associated with
Androgen Decline in Aging Male (ADAM), such as fatigue, depression,
decreased libido, sexual dysfunction, erectile dysfunction,
hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia,
osteopenia, osteoporosis, benign prostate hyperplasia, alterations
in mood and cognition and prostate cancer; c) treatment of
conditions associated with ADIF, such as sexual dysfunction,
decreased sexual libido, hypogonadism, sarcopenia, osteopenia,
osteoporosis, alterations in cognition and mood, depression,
anemia, hair loss, obesity, endometriosis, breast cancer, uterine
cancer and ovarian cancer; d) treatment and/or prevention of acute
and/or chronic muscular wasting conditions; e) preventing and/or
treating dry eye conditions; f) oral androgen replacement therapy;
and/or g) decreasing the incidence of, halting or causing a
regression of prostate cancer.
Polymorphs, solvates and salts of various drugs have been described
in the literature as imparting novel properties to the drugs.
Organic small drug molecules have a tendency to self-assemble into
various polymorphic forms depending on the environment that drives
the self assembly. Heat and solvent mediated effects can also lead
to changes that transform one polymorphic form into another.
Identifying which polymorphic form is the most stable under each
condition of interest and the processes that lead to changes in the
polymorphic form is crucial to the design of the drug manufacturing
process in order to ensure that the final product is in its
preferred polymorphic form. Different polymorphic forms of an
active pharmaceutical ingredient (API) can lead to changes in the
drug's solubility, dissolution rate, pharmacokinetics and
ultimately its bioavailability and efficacy in patients.
SUMMARY OF THE INVENTION
In one embodiment, the present invention relates to solid forms of
(R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and processes of preparation thereof. In some
embodiments such compounds are useful for their androgenic and
anabolic activity. (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide are selective androgen receptor modulators
(SARMs) useful for a) male contraception; b) treatment of a variety
of hormone-related conditions, for example conditions associated
with Androgen Decline in Aging Male (ADAM); c) treatment of
conditions associated with Androgen Decline in Female (ADIF); d)
treatment and/or prevention of chronic muscular wasting; and/or; e)
decreasing the incidence of, halting or causing a regression of
prostate cancer; f) oral androgen replacement and/or other clinical
therapeutic and/or diagnostic areas.
In one embodiment the present invention provides, a crystalline
form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hyd-
roxy-2-methylpropanamide compound.
In one embodiment the present invention provides, an anhydrous
crystalline form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound.
In another embodiment this invention provides, a composition
comprising a therapeutic amount of crystalline form of an anhydrous
crystalline form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2--
hydroxy-2-methylpropanamide and a suitable carrier or diluent.
In one embodiment this invention provides, a process for the
preparation of a crystalline form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide said process comprising dissolving (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide in at least one organic solvent at a temperature
of between about -20.degree. C. to +5.degree. C. under conditions
permissive to crystallization, thereby obtaining said crystalline
form.
In one embodiment, this invention provides, a paracrystalline (R)
or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound.
In another embodiment, this invention provides, a composition
comprising paracrystalline form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and a suitable carrier or diluent.
In one embodiment, this invention provides, a process for the
preparation of paracrystalline (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide comprising stirring a suspension of a crystalline
form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2--
hydroxy-2-methylpropanamide in water at ambient temperature of
about 20-30.degree. C. for at least 0.5 hours, to obtain a
paracrystalline compound.
In one embodiment this invention provides, a composition comprising
a mixture of crystalline and paracrystalline solid forms of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound and a suitable carrier or diluent.
BRIEF DESCRIPTION OF THE DRAWINGS
The subject matter regarded as the invention is particularly
pointed out and distinctly claimed in the concluding portion of the
specification. The invention, however, both as to organization and
method of operation, together with objects, features, and
advantages thereof, may best be understood by reference to the
following detailed description when read with the accompanying
drawings in which:
FIG. 1 schematically depicts the synthesis of racemic mixtures of
compound 1.
FIG. 2 schematically depicts the synthesis of the (S)-enantiomer of
compound S-1.
FIG. 3 schematically depicts the synthesis of the (R)-enantiomer of
compound R-1.
FIG. 4A-4D depict XRPD patterns for solid forms of Compound S-1.
4A--solid form A-batch P1 of compound S-1; 4B--solid form A-batch
P2 of compound S-1; 4C--solid form A-batch P3 of compound S-1;
4D--solid form B'-batch P4 of compound S-1.
FIG. 5A-5D are Raman spectra of sample batches P1-P4 of compound
S-1, respectively. The laser power setting was 100 mW, at a
resolution of 2 cm.sup.-1.
FIG. 6A-6D are TG-FTIR spectra of sample batches P1-P4 of compound
S-1, respectively. Conditions included a temperature range
operation in the dynamic mode of 25.degree. C./10.0/250.degree. C.,
in an N.sub.2 atmosphere.
FIG. 7A-7D are DSC spectra of sample batches P1-P4 of compound S-1,
respectively. The asterisk indicates a settling effect, an artifact
of the machinery used.
FIGS. 8A, 8B and 8C, are SEM micrographs of sample batches P1, P2
and P4 of compound S-1, respectively.
FIGS. 9A, 9B and 9C, are Dynamic Vapor Sorption (DVS) spectra of
sample batches, P1, P2, and P4 of compound S-1, respectively. 9A is
a DVS of form A. 9B is a DVS of form A. 9C is a DVS of form B'.
FIG. 10 demonstrates XRPD spectra of the compound obtained after
varying the S-1 concentration in given solvents, varying the
solvents, or a combination thereof. A--demonstrates XRPD spectra
after compound S-1, Form A, suspended in n-heptane, 108 mg/2.0 mL.
B--demonstrates XRPD spectra after compound S-1, Form B', suspended
in ethyl acetate+n-heptane 1:2 (v/v), 81 mg/1.7 mL. C--demonstrates
XRPD spectra after compound S-1, Form B' suspended in ethyl
acetate+n-pentane 1:2 (v/v), 101 mg/1.0 mL. D--demonstrates XRPD
spectra after compound S-1 Form A, suspended in ethyl
acetate+n-pentane 1:2 (v/v), 128 mg/2.0 mL. E--demonstrates XRPD
spectra after compound S-1 Form A, suspended in ethyl
acetate+n-pentane 1:2 (v/v), 112 mg/2.0 mL. F--demonstrates XRPD
spectra after compound S-1 Form A, suspended in methyl
acetate+n-pentane 1:2 (v/v), 126 mg/2.0 mL.
FIG. 11 shows the XRPD pattern representing the results of vapor
diffusion experiments conducted with compound S-1. A--demonstrates
XRPD spectra of compound S-1 in toluene and n-hexane at 23.degree.
C. for 2 days. B--shows a superimposed spectra of XRPD of batch P1
(Form A) and the XRPD obtained in FIG. 11A. C--demonstrates XRPD
spectra obtained for compound S-1 in acetic acid and water at
23.degree. C. for 7 days. D--shows a superimposed spectra of XRPD
of batch P1 (Form A) and the XRPD obtained in FIG. 11B.
FIG. 12 shows the XRPD pattern representing the results of
evaporation experiment wherein solutions of compounds were dried at
room temperature (dry N.sub.2 flow) without stifling.
12A--demonstrates XRPD pattern obtained of compound S-1 (batch P1)
in ethyl-acetate solution. 12B--demonstrates a superimposed spectra
of XRPD of batch P1 (Form A) and the XRPD obtained in FIG. 12A.
12C--demonstrates XRPD pattern obtained of compound S-1 (batch P1)
from THF, to provide form C. 12D--demonstrate XRPD patterns of a
mixture of form A (red, top) and form C (blue, bottom), as
presented in FIG. 12C.
FIG. 13 shows the XRPD spectra representing the results of
recrystallization from solution experiment wherein compound S-1 was
dissolved in different solvent system at room temperature and
cooled to +5.degree. C. or to -20.degree. C. 13A--demonstrates XRPD
spectra obtained of compound S-1 (batch P1) in
ethylacetate+n-heptane 1:1 (v/v). 13B--shows a superimposed spectra
of XRPD of batch P1 (Form A) and the XRPD obtained in FIG. 13A.
13C--demonstrates XRPD spectra obtained of compound S-1 (batch P1)
in acetonitrile+toluene 1:3 v/v. 13D--shows a superimposed spectra
of XRPD of batch P1 (Form A) and the XRPD obtained in FIG. 13B.
FIG. 14 shows the XRPD spectra representing the results of freeze
drying experiment. 14A--demonstrates XRPD spectra obtained of
compound S-1 (batch P-1) in 1-4-dioxane and cooled to -50.degree.
C. 14B--shows a superimposed spectra of XRPD of batch P1 (Form A)
and the XRPD obtained in FIG. 14A.
FIG. 15 demonstrates a DSC thermogram representing the results of a
drying experiment when compound S-1 (batch P4) was dried overnight
in a dry N.sub.2 atmosphere. The asterisk indicates a settling
effect, an artifact of the machinery used.
FIG. 16 demonstrates XRPD spectra representing the results of
relative stability experiments wherein suspension experiments were
carried out with mixtures of batches of S-1. 16A--demonstrates XRPD
spectra obtained from a mixture of batches of compound S-1 (P1,
P18, P24, P30, P37 and P38, all batches have a XRPD characteristics
of Form A) in ethylacetate+n-heptane 1:2 (v/v) 130 mg/2.0 mL. 16B
shows a superimposed spectra of XRPD of batch P1 (Form A) and the
XRPD obtained in FIG. 16A. 16C--demonstrates XRPD spectra obtained
from a mixture of batches of compound S-1 (P1 and P52 where batch
P1 is Form A and P52 is Form A+C) in ethylacetate+n-heptane 1:2
(v/v); (81+64) mg/2.0 mL. 16D shows a superimposed spectra of XRPD
of batch P1 (Form A) and the XRPD obtained in FIG. 16B.
FIG. 17 provides a DSC thermogram and XRPD pattern, representing
the results of water vapor sorption where S-1 (batch P1) was stored
in a glass tube under 96% r.h (relative humidity) at room
temperature. 17A--demonstrates the DSC results obtained for
compound S-1 batch P1 with no solvent after 11 weeks.
17B--demonstrates XRPD of compound S-1 batch P1 (form A) in water
after 19 h at 37.degree. C., resulting in formation of form B'.
17C--demonstrates XRPD of compound S-1 batch P1 (form A) in acetic
acid+water 1:2 (v/v) after 20 h at 23.degree. C. 17D--shows a DSC
thermogram of heating a sample of form A (black), cooling of the
sample after melting (grey) and reheating of the sample (white).
Heating rates were 10.degree. C./min while the cooling rate was
1.degree. C./min. Heating form A beyond the melting temperature
produces B'' which doesn't revert to A even when the sample is
cooled back down to ambient temperature. 17E--1.degree. C./min DSC
runs of form A (grey), B'' (black), mixture of A and D (white) and
mixture of B'' and D (dark grey). A and B'' can undergo
crystallization to D but only in the presence of D to act as seeds
for crystallization. 17F--DSC graphs for form A stored at ambient
temperature/100% RH for 7 days (light grey), 50.degree. C./0% RH
for 7 days (dark grey), and 50.degree. C./75% RH for 6 hours
(white) along with the DSC graph of the original sample (black).
17G--(a) DSC graphs of polymorph A seeded with form D and stored at
50.degree. C./75% RH. (b) DSC graphs of form A seeded with form D
and stored at 50.degree. C. in water.
FIG. 18 demonstrates XRPD patterns of a superimposed spectra of
XRPD of form A (top) and form D (bottom) of compound S-1.
FIG. 19 demonstrates a DSC thermograms of forms A and D.
FIG. 20 Thermogravimetric analysis (TGA) graph of the toluene
solvate (red) and form D (black).
DETAILED DESCRIPTION OF THE INVENTION
In some embodiments, the present invention provides solid forms of
(R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and processes of preparation of the same. This
invention also provides pharmaceutical compositions comprising the
solid forms of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hyd-
roxy-2-methyl propanamide, and uses thereof.
(R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hyd-
roxy-2-methylpropanamide are androgen receptor targeting agents
(ARTA), which demonstrate androgenic and anabolic activity. In some
embodiments, the methyl propionamides as herein described are
selective androgen receptor modulators (SARM), which in some
embodiments are useful for a) male contraception; b) treatment of a
variety of hormone-related conditions, for example conditions
associated with Androgen Decline in Aging Male (ADAM), such as
fatigue, depression, decreased libido, sexual dysfunction, erectile
dysfunction, hypogonadism, osteoporosis, hair loss, anemia,
obesity, sarcopenia, osteopenia, osteoporosis, benign prostate
hyperplasia, alterations in mood and cognition and prostate cancer;
c) treatment of conditions associated with Androgen Decline in
Female (ADIF), such as sexual dysfunction, decreased sexual libido,
hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in
cognition and mood, depression, anemia, hair loss, obesity,
endometriosis, breast cancer, uterine cancer and ovarian cancer; d)
treatment and/or prevention of chronic muscular wasting; e)
decreasing the incidence of, halting or causing a regression of
prostate cancer; f) oral androgen relacement and/or other clinical
therapeutic and/or diagnostic areas.
In some embodiments, this invention provides polymorphic solid
forms of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hyd-
roxy-2-methylpropanamide compounds of this invention. In one
embodiment the term "polymorph" refers to a specific form of the
SARM compounds of this invention, for example, polymorphs may
represent crystalline forms that can vary in pharmaceutically
relevant physical properties between one form and another, for
example under different crystallization conditions, environmental
conditions, hygroscopic activity of the compounds, etc.
In one embodiment, this invention provides, a crystalline form of
(R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound.
In one embodiment, this invention provides, a crystalline form of
anhydrous (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound.
In one embodiment, this invention provides, a crystalline form of
anhydrous
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2--
hydroxy-2-methylpropanamide compound.
In another embodiment, the crystalline form of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide (compound S-1), is characterized by: a. an X-Ray
Powder diffraction pattern comprising peaks at .degree.2.theta. (d
value .ANG.) angles of about 5.6 (15.9), 7.5 (11.8), 8.6 (10.3),
9.9 (8.9), 12.4 (7.1), 15.0 (5.9), 16.7 (5.3), 17.3 (5.1), 18.0
(4.9), 18.5 (4.8), 19.3 (4.6), 19.8 (4.5), 20.6 (4.3), 21.8 (4.1),
22.3 (4.0), 23.4 (3.8), 23.9 (3.7), 24.6 (3.6), 24.9 (3.6), 25.4
(3.5), 26.0 (3.4), 26.5 (3.4), 27.8 (3.2); and b. a melting point
of about 80.degree. C.
According to this aspect and in another embodiment, such a
crystalline form of compound S-1, having all or part of the
characteristics listed in (a) and (b) is referred to herein as
crystalline Form A.
In another embodiment, the solubility of Form A in water is between
20-30 mg/L at 22.degree. C. In another embodiment, the solubility
of Form A in water is between 23-27 mg/L at 22.degree. C.
In one embodiment, this invention provides a crystalline form of an
(R)--N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-
-methylpropanamide (compound R-1), wherein said crystalline form is
obtained by methods similar to that of the S isomer, as described
herein. In some embodiments, such a crystalline form of compound
R-1, is structurally related and/or possesses similar
characteristics to that of compound S-1.
In one embodiment this invention provides a paracrystalline (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound.
In one embodiment this invention provides a paracrystalline
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound.
In one embodiment, the paracrystalline form of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide (compound S-1) is characterized by: a. an X-Ray
Powder diffraction pattern displaying a broad halo with two
harmonic peaks between 15-25 .degree.2.theta. and b. a glass
transition point of about 55.degree. C.
According to this aspect and in another embodiment, such a
paracrystalline form of compound S-1, having all or part of the
characteristics listed in (a) and (b) is referred herein as
paracrystalline form B'.
In one embodiment the term "paracrystalline" refers to the state of
material exhibiting short-range order without long-range order such
as liquid crystals or other type of lamellar structures. In one
embodiment, the paracrystalline form is a liquid crystal. In
another embodiment, the Form B' of compound S-1 is a
paracrystalline. In another embodiment, form A of S-1 may convert
in whole or in part to paracrystalline Form B' of S-1.
In another embodiment, the solubility of Form B' in water is
between 20-30 mg/L at 22.degree. C. In another embodiment, the
solubility of Form B' in water is between 23-27 mg/L at 22.degree.
C.
In one embodiment, this invention provides an paracrystalline form
B'' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide, characterized by: a. an X-Ray Powder diffraction
pattern displaying a broad halo with two harmonic peaks between
15-25.degree.2.theta. and b. a glass transition point of about
55.degree. C.
In one embodiment, this invention provides a crystalline Form C of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide characterized by: a. an X-Ray Powder diffraction
pattern comprising unique peaks at .degree.2.theta. (d value .ANG.)
angles of about 6.9 (12.8), 9.5 (9.3), 13.5 (6.6), 16.0 (5.6), 22.8
(3.9).
In another embodiment, crystalline Form C of compound S-1 is
obtained as a mixture of Form A and C, by evaporating A out of
THF.
In one embodiment, this invention provides a crystalline Form D of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide characterized by: a. an X-Ray powder diffraction
pattern comprising unique peaks at .degree.2.theta. (d value .ANG.)
angles of about 4.4 (19.9), 8.5 (10.4), 8.8 (10.0), 11.3 (7.8),
12.7 (6.9), 13.8 (6.4), 14.4 (6.1), 14.6 (6.0), 15.1 (5.8), 16.1
(5.5), 16.6 (5.3), 16.9 (5.2), 18.0 (4.9), 18.7 (4.7), 19.0 (4.6),
19.4 (4.55), 20.8 (4.25), 22.1 (4.0), 22.7 (3.9), 23.1 (3.8), 23.4
(3.8), 24.7 (3.6), 24.9 (3.56), 25.3 (3.51), 27.8 (3.2), 29.3
(3.0); and b. a melting point of about 130.degree. C.
In another embodiment, crystalline Form D of compound S-1 is stable
at 50.degree. C./75% RH (Relative Humidity) as well as the other
conditions of ambient/75% RH, ambient/100% RH, 30.degree. C./75% RH
and 50.degree. C./0% RH.
In another embodiment the characteristics of the different solid
forms of S-1 are presented in Example 2 and FIGS. 4-20.
Solid forms of this invention can be analysed by any method known
in the art for example and in one embodiment, X-ray powder
diffraction. In another embodiment analysis of the solid forms of
this invention may comprise Raman Spectroscopy. In another
embodiment analysis of the solid forms of this invention may
comprise TG-FTIR (thermo gravimetric fourier transform infrared).
In another embodiment analysis of the solid forms of this invention
may comprise FT-Raman (fourier transform-Raman). In another
embodiment analysis of the solid forms of this invention may
comprise DSC (differential scanning calorimetry). In another
embodiment analysis of the solid forms of this invention may
comprise DVS (dynamic vapor sorption). In another embodiment
analysis of the solid forms of this invention may comprise SEM
(Scanning electron microscopy).
In one embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A and B' in a ratio of between about
95:5 to 85:15, respectively. In another embodiment, the ratio is
between about 85:15 to 75:25, respectively. In another embodiment,
the ratio is between about 75:25 to 65:35, respectively. In another
embodiment, the ratio is between about 95:5 to 90:10, respectively.
In another embodiment, the ratio is between about 90:10 to 85:15,
respectively. In another embodiment, the ratio is between about
97:3 to 93:7, respectively. In another embodiment, the ratio is
between about 85:15 to 80:20. In another embodiment, the ratio is
between about 70:20 to 60:20. In another embodiment, the ratio is
50:50, respectively.
In one embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A, B' and C in a ratio of between
about 90:5:5 to 80:10:10, respectively. In another embodiment, the
ratio is between about 80:10:10 to 75:15:10, respectively. In
another embodiment, the ratio is between about 95:3:2 to 90:7:3,
respectively. In another embodiment, the ratio is between about
75:15:10 to 65:20:15. In another embodiment, the ratio is between
about 70:20:10 to 60:20:20.
In one embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A, B' and D in a ratio of between
about 5:5:90 to 10:10:80, respectively. In another embodiment, the
ratio is between about 10:10:80 to 10:15:75, respectively. In
another embodiment, the ratio is between about 2:3:95 to 3:7:90,
respectively. In another embodiment, the ratio is between about
10:15:75 to 15:20:65. In another embodiment, the ratio is between
about 10:20:70 to 20:20:60.
In one embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A and C in a ratio of between about
98:2 to 95:5, respectively. In one embodiment, this invention
provides a polymorphic mixture comprising crystalline forms A and C
in a ratio of between about 95:5 to 90:10, respectively. In one
embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A and C in a ratio of between about
90:10 to 85:15, respectively. In one embodiment, this invention
provides a polymorphic mixture comprising crystalline forms A, and
C in a ratio of between about 85:15 to 80:20, respectively. In one
embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A, and C in a ratio of about 50:50,
respectively.
In one embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A and D in a ratio of between about
2:98 to 5:95, respectively. In one embodiment, this invention
provides a polymorphic mixture comprising crystalline forms A and D
in a ratio of between about 5:95 to 10:90, respectively. In one
embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A and D in a ratio of between about
10:90 to 15:85, respectively. In one embodiment, this invention
provides a polymorphic mixture comprising crystalline forms A, and
D in a ratio of between about 15:85 to 20:80, respectively. In one
embodiment, this invention provides a polymorphic mixture
comprising crystalline forms A, and D in a ratio of about 50:50,
respectively.
In one embodiment, this invention provides a polymorphic mixture
comprising crystalline forms B' and D in a ratio of between about
2:98 to 5:95, respectively. In one embodiment, this invention
provides a polymorphic mixture comprising crystalline forms B' and
D in a ratio of between about 5:95 to 10:90, respectively. In one
embodiment, this invention provides a polymorphic mixture
comprising crystalline forms B' and D in a ratio of between about
10:90 to 15:85, respectively. In one embodiment, this invention
provides a polymorphic mixture comprising crystalline forms B', and
D in a ratio of between about 15:85 to 20:80, respectively. In one
embodiment, this invention provides a polymorphic mixture
comprising crystalline forms B', and D in a ratio of about 50:50,
respectively.
In one embodiment, this invention provides a polymorphic mixture
comprising crystalline forms B' and C in a ratio of between about
98:2 to 95:5, respectively. In one embodiment, this invention
provides a polymorphic mixture comprising crystalline forms B' and
C in a ratio of between about 95:5 to 90:10, respectively. In one
embodiment, this invention provides a polymorphic mixture
comprising crystalline forms B' and C in a ratio of between about
90:10 to 85:15, respectively. In one embodiment, this invention
provides a polymorphic mixture comprising crystalline forms B' and
C in a ratio of between about 85:15 to 80:20, respectively. In one
embodiment, this invention provides a polymorphic mixture
comprising crystalline forms B' and C in a ratio of about 50:50,
respectively.
In another embodiment, the ratio between crystalline form A to
crystalline form B' is between about 95:5 to 85:15. In another
embodiment, the ratio between crystalline form A to crystalline
form B' is between about 98:2 to 95:5. In another embodiment, the
ratio between crystalline form A to crystalline form B' is between
about 85:15 to 75:25. In another embodiment, the ratio between
crystalline form A to crystalline form B' is between about 75:25 to
65:35 respectively.
In one embodiment a sample of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide may comprise a mixture of solid form A, B', B'',
C and D. In another embodiment the percentage of several solid
forms in a sample (for example the percentage of solid form A and B
in a sample) can be determined by running a Modulated DSC
(Differential Scanning calorimetry) at a heating rate of 3.degree.
C./min from 10.degree. C. to 130.degree. C., followed by linear
integration of the solid form A and/or solid form B to obtain the
enthalpy of each.
In one embodiment the solid form of a SARM compound can influence
its bioavailability, stability, processability and ease of
manufacture and uses thereof are to be considered part of this
invention.
In one embodiment, this invention provides a process for the
preparation of a crystalline form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide comprising dissolving amorphous (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide in at least one organic solvent at a temperature
of between about -20.degree. C. to +30.degree. C. under conditions
permissive to crystallization, thereby obtaining the crystalline
form.
In one embodiment, this invention provides a process for the
preparation of a crystalline form A of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide comprising dissolving amorphous
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide in at least one organic solvent at a temperature
of between about -20.degree. C. to +30.degree. C. under conditions
permissive to crystallization, thereby obtaining the crystalline
form.
In another embodiment, the temperature for crystallization of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide, is about 5.degree. C. In another embodiment, the
temperature is of about -20.degree. C. In another embodiment, the
temperature is of about 20.degree. C. In another embodiment, the
temperature is between about 20 to 50.degree. C. In another
embodiment, the temperature is about -10 to 0.degree. C. In another
embodiment, the temperature is about 0 to 5.degree. C. In another
embodiment, the temperature is about -10 to -20.degree. C.
In another embodiment, form A of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide (compound S-1) is prepared by crystallization
from an organic solvent comprising a mixture of solvents. In
another embodiment the mixture comprises two solvents in a 1:2 v/v
ratio, respectively. In another embodiment the mixture comprises
two solvents in a 1:3 v/v ratio, respectively. In another
embodiment the mixture comprises two solvents in a 1:4 v/v ratio,
respectively. In another embodiment the mixture comprises ethyl
formate and pentane in a 1:2 v/v ratio, respectively. In another
embodiment, the mixture comprises methyl acetate and pentane in a
1:2 v/v ratio, respectively. In another embodiment the mixture
comprises ethylacetate and n-hexane. In another embodiment the
mixture comprises toluene and n-hexane. In another embodiment the
mixture comprises dichloromethane and n-hexane. In another
embodiment the mixture comprises acetic acid and water in a 1:2 v/v
ratio. In another embodiment, form A is prepared by crystallization
from a solvent/antisolvent mixture at ambient temperature. In
another embodiment, ethyl acetate, ethanol, dichloromethane or
acetonitrile are the solvents and n-hexane, n-pentane, n-heptane
and cyclohexane etc. are used as antisolvents. In another
embodiment the solvent/antisolvent ratios are between 1:2 and
1:3.
In another embodiment, the crystalline form A of compound S-1 is
prepared by forming a suspension of a paracrystalline form of
compound of formula S-1 in a solvent/antisolvent mixture. In
another embodiment solid form A is prepared by forming a suspension
of a paracrystalline form of compound of formula S-1 in
ethylacetate and heptane mixture in a 1:2 v/v ratio, respectively.
In another embodiment, solid form A is prepared by forming a
suspension of a paracrystalline form of compound of formula S-1 in
a mixture of ethylacetate and pentane in a 1:2 v/v ratio,
respectively. In another embodiment, the crystalline form A of
compound S-1 is prepared by forming a suspension of form B' in a
solvent/antisolvent mixture at concentrations above the saturation
limit at 23.degree. C. for several hours followed by drying to
obtain form A.
In another embodiment, form D of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide (compound S-1) is prepared by crystallization
from solvent/antisolvent mixture at 50.degree. C. using ethyl
acetate and cyclohexane as the solvent and antisolvents,
respectively. In another embodiment, form D is prepared from other
polymorphic forms by "seeding" the sample with a small amount of D
and storing it at 110.degree. C./0% RH for 7 days or at 50.degree.
C. in water for 24 hours followed by drying. In another embodiment,
heating forms A and/or B'' to 110.degree. C. in the presence of D
causes the A and B'' forms to rearrange into form D. In another
embodiment, form D in the presence of moisture acts as the seed for
the crystallization process and drives the transformation of forms
A and B' into D.
In another embodiment, FIG. 17G shows the time evolution of
polymorph A seeded with a small amount of D at 50.degree. C./75%
RH. The amount of polymorph D initially added to the sample is very
small that it isn't detectable by the DSC with heating rate of
10.degree. C./min. After 24 hours, most of the polymorph form A has
been converted to B' but a small amount of sample has also been
converted to D and the amount of sample in D increases over time.
The transformation process is speeded up in FIG. 17G by storing the
sample in water at 50.degree. C. Form A has been converted to both
B' and D after 6 hours but the sample is predominantly in form D by
24 hours.
In one embodiment this invention provides a process for the
preparation of paracrystalline (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide comprising stifling a suspension of a crystalline
form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2--
hydroxy-2-methylpropanamide in water at ambient temperature of
about 20-30.degree. C. for at least 0.5 hours, to obtain a
paracrystalline compound.
In one embodiment this invention provides a process for the
preparation of paracrystalline form B' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide comprising stifling a suspension of a crystalline
form of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-
-2-methylpropanamide in water at ambient temperature of about
20-30.degree. C. for at least 0.5 hours, to obtain a
paracrystalline compound.
In one embodiment this invention provides a process for the
preparation of paracrystalline form B' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide comprising stirring a suspension of a crystalline
form A of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-
-2-methylpropanamide in water at ambient temperature of about
20-30.degree. C. for at least 0.5 hours, to obtain a
paracrystalline compound. In another embodiment, paracrystalline
form B' is prepared by stifling a suspension of crystalline form A
at 50.degree. C. in water for 24 h. In another embodiment
paracrystalline form B' is prepared by stifling a suspension of
crystalline form A at 37.degree. C. overnight to obtain
paracrystalline form B'.
In one embodiment solid form B' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide is prepared by storage of solid form A at
40.degree. C. and 75% relative humidity (r.h.) for 1-2 h. In
another embodiment, solid form A is stored at 40.degree. C. and 75%
r.h. for 2-4 h. In another embodiment, solid form A is stored at
40.degree. C. and 75% r.h. for 4-10 h. In another embodiment, solid
form A is stored at 40.degree. C. and 75% r.h. for 10-15 h. In
another embodiment, solid form A is stored at 40.degree. C. and 75%
r.h. for 15-24 h.
In another embodiment, solid form A is stored at 40.degree. C. and
75% r.h. for 24 h. In another embodiment, solid form A is stored at
40.degree. C. and 75% r.h. for 30 days.
In one embodiment solid form B' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide is prepared by storage of solid form A at
40.degree. C. and 75% relative humidity (r.h.). In another
embodiment, solid form A is stored at a temperature range of about
of 30-40.degree. C. and relative humidity range of about 50-75%. In
another embodiment, solid form A is stored at a temperature range
of about of 40-50.degree. C. and a relative humidity of about
60-80%. In another embodiment, solid form A is stored at a
temperature range of about 40-50.degree. C. and a relative humidity
of about 60-80%.
In one embodiment, form B' is assigned as a lyotropic liquid
crystalline form due to its solvent mediated formation.
In one embodiment liquid crystalline form B'' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide is prepared by melting or heating solid form A of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide to 80.degree. C. followed by cooling.
In one embodiment form B'' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide is prepared by melting or heating to 130.degree.
C. solid form D of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide followed by cooling.
In one embodiment, evaporation of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide from solvents such as ethanol without an
antisolvent yield form B''.
In one embodiment, form B'' is assigned as a thermotropic liquid
crystalline form from its thermal method of preparation.
In one embodiment this invention provides a process for the
preparation of solid form C of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide comprising dissolving crystalline form A of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide in THF, followed by evaporation to obtain solid
form C.
In another embodiment, form C is obtained as a mixture with form
A.
In one embodiment this invention provides a process for the
preparation of toluene solvate solid form of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide comprising using any solvent/antisolvent
crystallization method that uses toluene as the antisolvent.
In another embodiment, the toluene solvate solid form has a melting
point about 100.degree. C. with the enthalpy of melting 70.+-.5
J/g.
In another embodiment, thermogravimetric analysis (TGA) graph of
the toluene solvate in FIG. 20 shows that the toluene content in
the solvate is about 7% which corresponds to one toluene molecule
for every three molecules of S-1. In another embodiment the toluene
molecules reside inside the unit cell structure rather than in
channels or layers outside the lattice. In another embodiment, the
toluene solvate solid form is the most stable form in toluene.
In some embodiments, crystalline forms of the SARMs of this
invention comprise alteration of a given crystalline form to one
structurally similar, yet not identical to the original form. In
one embodiment, such changes in crystalline forms may produce one
that is more structurally stable than the original form. In some
embodiments, the crystalline forms of this invention comprise
altered crystalline forms, as well as original forms, in a single
preparation. In some embodiments, such altered crystalline forms
may comprise a small percentage of the whole SARM compound
preparation, for example, up to 1%, or in another embodiment, up to
5%, or up to 10%, or up to 15%, or up to 25% of the preparation. In
another embodiment, such altered forms may comprise the majority of
the SARM compound preparation and may comprise 55%, or in another
embodiment, 65%, or in another embodiment, 75%, or 80%, or 85%, or
90%, or 95% or up to 100% of the SARM compound preparation. In one
embodiment, the favorable crystalline form is thermodynamically
favorable. In another embodiment the crystalline favorable form is
a result of a change in humidity. In another embodiment the
crystalline favorable form is a result of a change in temperature.
In another embodiment the crystalline favorable form is a result of
a change in solvents.
In some embodiments, the process for the preparation of polymorph
of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-
-2-methylpropanamide compounds yield various crystalline forms. In
one embodiment the process yields a mixture of
crystalline/paracrystalline forms A, B', C and D. In one embodiment
the process yields a mixture of crystalline/paracrystalline forms
A, B', B'', C and D. In another embodiment, the process yields a
mixture of crystalline forms A and C. In another embodiment, the
process yields a mixture of crystalline/paracrystalline forms A and
B'. In another embodiment, the process yields a mixture of
crystalline forms A and D. In another embodiment, the process
yields a mixture of crystalline/paracrystalline forms B' and D. In
another embodiment, the process yields a mixture of
crystalline/paracrystalline forms B'' and D. In another embodiment,
the process yields a mixture of crystalline forms C and D. In
another embodiment, the process yields a mixture of
crystalline/paracrystalline forms B' and C. In another embodiment,
the process yields a mixture of crystalline/paracrystalline forms A
and B''. In another embodiment, the process yields a mixture of
paracrystalline forms B' and B''. In another embodiment, the
process yields a mixture of crystalline/paracrystalline forms C and
B''. In another embodiment, the process yields a mixture of
crystalline/paracrystalline forms A, C and B''. In another
embodiment, the process yields a mixture of
crystalline/paracrystalline forms A, D and B''. In another
embodiment, the process yields a mixture of
crystalline/paracrystalline forms B', B'' and C. In another
embodiment, the process yields a mixture of
crystalline/paracrystalline forms A, B' and B''. In another
embodiment, the process yields a mixture of
crystalline/paracrystalline forms D, B' and B''.
In one embodiment, the solid form compounds of this invention are
dried from solution by vacuum at room temperature, followed by
gradually increasing the temperature. In another embodiment, the
solid form compounds of this invention are filtered from
solution
In one embodiment, the term "ambient temperature" refers to room
temperature. In another embodiment, the term "ambient temperature"
refers to 20-25.degree. C. In another embodiment, "ambient
temperature" refers to 25-30.degree. C.
In another embodiment, form D is the most thermodynamically stable
polymorph in both dry conditions and in the presence of water at
ambient temperature up to its melting point of 130.degree. C. In
another embodiment, FIG. 19 depicts a differential scanning
calorimeter (DSC) thermogram of form A and form D, where form A
melts at about 80.degree. C. and form D melts at about 130.degree.
C. In another embodiment, the enthalpy of melting for form A is
40.+-.5 J/g while the enthalpy of melting for form D is 75.+-.5
J/g.
In another embodiment form A is stable in its A form for at least 7
days under storage conditions of ambient temperature/75% RH
(Relative Humidity), ambient temperature/100% RH, 30.degree. C./75%
RH and 50.degree. C./0% RH. In another embodiment, form A converts
to B' when stored at 50.degree. C./75% RH. In another embodiment,
form A converts to B'when stored at 40.degree. C./75% RH within one
month. In another embodiment form A stored at 25.degree. C./60% RH
and 30.degree. C./65% RH is stable through 36 months and 9 months
respectively.
In one embodiment, (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide are prepared by chiral synthesis.
In one embodiment, the
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide may be prepared by a process according to the
following synthetic scheme:
##STR00001##
In one embodiment, the process described in the above scheme
comprises reacting the acylanilide in step 5 with the cyanophenol,
and such reaction may be conducted in the presence of potassium
carbonate, sodium carbonate, or cesium carbonate. In one
embodiment, reaction in the presence of potassium carbonate
unexpectedly results in a product with fewer impurities as compared
to a reaction conducted in the presence of cesium carbonate. This
represents an improved and more efficient synthetic process for
producing an end product, minimizing the need for additional
purification steps. This finding is also advantageous to the
production of other compounds such as 6, 9, 12, and 14 below.
In one embodiment, this invention provides a process for preparing
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide, said process comprising the steps of: a)
preparing a carboxylic acid of formula 1 by ring opening of a
cyclic compound of formula 2 in the presence of HBr
##STR00002## b) reacting an amine of formula 3:
##STR00003## with the carboxylic acid of formula 2 in the presence
of a coupling reagent, to produce an amide of formula 4
##STR00004## and c) reacting the amide of formula 4 with a compound
of formula 5:
##STR00005## wherein step (c) is carried out in the presence of
potassium carbonate and tetrahydrofuran.
In one embodiment, this invention provides a process for preparing
a compound of formula 6:
##STR00006## said process comprising the steps of: a) preparing a
carboxylic acid of formula 1 by ring opening of a cyclic compound
of formula 2 in the presence of HBr
##STR00007## b) reacting an amine of formula 7:
##STR00008## with the carboxylic acid of formula 2 in the presence
of a coupling reagent, to produce an amide of formula 8:
##STR00009## and c) reacting the amide of formula 8 with a compound
of formula 5:
##STR00010## wherein step (c) is carried out in the presence of
potassium carbonate and tetrahydrofuran.
In one embodiment, this invention provides a process for preparing
a compound of formula 9:
##STR00011## said process comprising the steps of: a) preparing a
carboxylic acid of formula 1 by ring opening of a cyclic compound
of formula 2 in the presence of HBr
##STR00012## b) reacting an amine of formula 3:
##STR00013## with the carboxylic acid of formula 2 in the presence
of a coupling reagent, to produce an amide of formula 4
##STR00014## and c) reacting the amide of formula 4 with a compound
of formula 10:
##STR00015## wherein step (c) is carried out in the presence of
potassium carbonate and tetrahydrofuran.
In one embodiment, this invention provides a process for preparing
a compound of formula 12:
##STR00016## said process comprising the steps of: a) preparing a
carboxylic acid of formula 1 by ring opening of a cyclic compound
of formula 2 in the presence of HBr
##STR00017## b) reacting an amine of formula 3:
##STR00018## with the carboxylic acid of formula 2 in the presence
of a coupling reagent, to produce an amide of formula 4
##STR00019## and c) reacting the amide of formula 4 with a compound
of formula 13:
##STR00020## wherein step (c) is carried out in the presence of
potassium carbonate and tetrahydrofuran.
In one embodiment, this invention provides a process for preparing
a compound of formula 14:
##STR00021## X is O, NH, Se, PR, or NR; T is OH, OR, NHCOCH.sub.3,
or NHCOR; Z is NO.sub.2, CN, COOH, COR, NHCOR or CONHR; Y is
CF.sub.3, F, I, Br, Cl, CN, CR.sub.3 or SnR.sub.3; Q is alkyl,
halogen, CF.sub.3, CN, CR.sub.3, SnR.sub.3, NR.sub.2, NHCOCH.sub.3,
NHCOCF.sub.3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH.sub.3,
NHCSCF.sub.3, NHCSR NHSO.sub.2CH.sub.3, NHSO.sub.2R, OR, COR, OCOR,
OSO.sub.2R, SO.sub.2R, SR; or Q together with the benzene ring to
which it is attached is a fused ring system represented by
structure A, B or C:
##STR00022## R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl,
CH.sub.2F, CHF.sub.2, CF.sub.3, CF.sub.2CF.sub.3, aryl, phenyl,
halogen, alkenyl or OH; and R.sub.1 is CH.sub.3, CH.sub.2F,
CHF.sub.2, CF.sub.3, CH.sub.2CH.sub.3, or CF.sub.2CF.sub.3; said
process comprising the steps of: a) preparing a carboxylic acid of
formula 15 by ring opening of a cyclic compound of formula 16 in
the presence of HBr
##STR00023## wherein L, R.sub.1 and T are as defined above, and
T.sub.1 is O or NH; b) reacting an amine of formula 17:
##STR00024## wherein Z and Y are as defined above, with the
carboxylic acid of formula 17 in the presence of a coupling
reagent, to produce an amide of formula 18
##STR00025## and c) coupling the amide of formula II with a
compound of formula 19:
##STR00026## wherein Q and X are as defined above and wherein step
(c) is carried out in the presence of potassium carbonate and
tetrahydrofuran.
In one embodiment, crystalline and paracrystalline forms of this
invention are prepared by any process which may yield the same,
such as, but not limited to those exemplified herein, as will be
appreciated by one skilled in the art. In one embodiment, such a
process will utilize a starting material for the preparation of
crystalline and paracrystalline forms of this invention, which in
turn, in some embodiments is prepared according to the method
schematically depicted hereinabove. In some embodiments, preparing
the starting material comprises specific reaction of the amide of
formula 4 with a compound of formula 5 in the presence of potassium
carbonate and a polar solvent, such as for example and in some
embodiments, tetrahydrofuran, results in the production of a highly
pure preparation, which in turn may enhance the rate of
crystallization. In some embodiments, use of the pure preparation
as described herein, depending upon crystallization conditions
employed may result in varied ratio of crystalline forms obtained.
In some embodiments, use of the pure preparation as described
herein, depending upon crystallization conditions employed may
result in varied ratio of crystalline forms, and the rate at which
such forms are produced.
In one embodiment, the process further comprises the step of
converting the selective androgen receptor modulator (SARM)
compound (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide to its analog, isomer, polymorph, polymorph form
A, paracrystalline form B', solvate, metabolite, derivative,
pharmaceutically acceptable salt, pharmaceutical product, N-oxide,
hydrate, hemi-hydrate or any combination thereof.
In one embodiment, this invention provides a process for preparing
an analog of a selective androgen modulator compound of this
invention. In another embodiment, this invention provides a process
for preparing an isomer of a selective androgen modulator compound
of this invention. In another embodiment, this invention provides a
process for preparing a metabolite of a selective androgen
modulator compound of this invention. In another embodiment, this
invention provides a process for preparing a derivative of a
selective androgen modulator compound of this invention. In another
embodiment, this to invention provides a process for preparing a
pharmaceutically acceptable salt of a selective androgen modulator
compound of this invention. In another embodiment, this invention
provides a process for preparing a pharmaceutical product of a
selective androgen modulator compound of this invention. In another
embodiment, this invention provides a process for preparing an
N-oxide of a selective androgen modulator compound of this
invention. In another embodiment, this invention provides a process
for preparing a hydrate of a selective androgen modulator compound
of this invention. In another embodiment, this invention provides a
process for preparing a polymorph of a selective androgen modulator
compound of this invention. In another embodiment, this invention
provides a process for preparing a polymorph form A as herein
described of a selective androgen modulator compound of this
invention. In another embodiment, this invention provides a process
for preparing a paracrystalline form B' as herein described of a
selective androgen modulator compound of this invention. In another
embodiment, this invention provides a process for preparing a
polymorph form C as herein described of a selective androgen
modulator compound of this invention. In another embodiment, this
invention provides a process for preparing a polymorph form D as
herein described of a selective androgen modulator compound of this
invention. In another embodiment, this invention provides a process
for preparing a paracrystalline form of a selective androgen
modulator compound of this invention. In another embodiment, this
invention provides a process for preparing a solvate of a selective
androgen modulator compound of this invention. In another
embodiment, this invention provides a process for preparing a
combination of any of an analog, isomer, metabolite, derivative,
polymorph, polymorph form A, paracrystalline form B',
paracrystalline, solvate, pharmaceutically acceptable salt, N-oxide
and/or hydrates of a selective androgen modulator compound of this
invention. In one embodiment this invention comprises any compound
thus prepared.
In one embodiment, the term "isomer" includes, but is not limited
to, optical isomers and analogs, structural isomers and analogs,
conformational isomers and analogs, and the like.
In one embodiment, the SARMs are the pure (R)-enantiomer. In
another embodiment, the SARMs are the pure (S) enantiomer. In
another embodiment, the SARMs are a mixture of the (R) and the (S)
enantiomers. In another embodiment, the SARMs are a racemic mixture
comprising an equal amount of the (R) and the (S) enantiomers. In
one embodiment, the process of the present invention further
provides a step of converting the SARM compound into its optically
active isomer.
In one embodiment, separation of the optically-active (R)
enantiomer or (S) enantiomer, from the racemic SARM compounds of
this invention comprises crystallization techniques. In another
embodiment, the crystallization techniques include differential
crystallization of enantiomers. In another embodiment, the
crystallization techniques include differential crystallization of
diastereomeric salts (tartaric salts or quinine salts). In another
embodiment, the crystallization techniques include differential
crystallization of chiral auxiliary derivatives (menthol esters,
etc). In another embodiment, separation of the optically-active (R)
enantiomer or (S) enantiomer, from the racemic SARM compounds of
this invention comprises reacting the racemate mixture with another
chiral group, forming of a diastereomeric mixture followed by
separation of the diastereomers and removing the additional chiral
group to obtain pure enantiomers. In another embodiment, separation
of the optically-active (R) enantiomer or (S) enantiomer, from the
racemic SARM compounds of this invention comprises chiral
synthesis. In another embodiment, separation of the
optically-active (R) enantiomer or (S) enantiomer, from the racemic
SARM compounds of this invention comprises biological resolution.
In another embodiment, separation of the optically-active (R)
enantiomer or (S) enantiomer, from the racemic SARM compounds of
this invention comprises enzymatic resolution. In another
embodiment, separation of the optically-active (R) enantiomer or
(S) enantiomer, from the racemic SARM compounds of this invention
comprises chromatographic separation using a chiral stationary
phase. In another embodiment, separation of the optically-active
(R) enantiomer or (S) enantiomer, from the racemic SARM compounds
of this invention comprises affinity chromatography. In another
embodiment, separation of the optically-active (R) enantiomer or
(S) enantiomer, from the racemic SARM compounds of this invention
comprises capillary electrophoresis. In another embodiment,
separation of the optically-active (R) enantiomer or (S)
enantiomer, from the racemic SARM compounds of this invention
comprises forming an ester group of the hydroxyl group of the
chiral carbon with an optically-active acid, for example
(-)-camphanic acid, separating the diastereomers esters, thus
obtained, by fractional crystallization or preferably, by
flash-chromatography, and then hydrolyzing each separate ester to
the alcohol.
In another embodiment the S-enantiomer of SARM compound of this
invention can be converted to the R-enantiomer or to its racemate.
In another embodiment the R-enantiomer of SARM compound of this
invention can be converted to the S-enantiomer or to its racemate.
In one embodiment, one enantiomer can be converted to the other
enantiomer or its racemate by using a chiral reactant, a solvent, a
biocatalyst, chiral catalyst, asymmetric hydrogenation, an enzyme,
or combination thereof.
In some embodiments the solid compounds of this invention comprise
solvates. In one embodiment the term "solvate" refers to solvents
combined with SARM compounds, for example, a solvate of
ethylacetate, which is part of a polymorph structure of the SARM
compound. Such solvents include ethanol, acetone, ethylacetate,
THF, acetonitrile, dichloromethane, 1,4-dioxane, acetic acid,
toluene, water, n-heptane, toluene, n-pentane TBME, or any
combination thereof.
In another embodiment, the process of the present invention further
provides a step of converting the SARM compound into its
pharmaceutically acceptable salt. In one embodiment,
pharmaceutically acceptable salts include salts of
amino-substituted compounds with organic and inorganic acids, for
example, citric acid and hydrochloric acid. The invention also
includes N-oxides of the amino substituents of the compounds
described herein. Pharmaceutically acceptable salts can also be
prepared from phenolic compounds by treatment with inorganic bases,
for example, sodium hydroxide. Also, esters of the phenolic
compounds can be made with aliphatic and aromatic carboxylic acids,
for example, acetic acid and benzoic acid esters.
The invention includes "pharmaceutically acceptable salts" of the
compounds of this invention, which may be produced, by reaction of
a compound of this invention with an acid or base.
Suitable pharmaceutically-acceptable salts of amines of Formula I
may be prepared from an inorganic acid or from an organic acid. In
one embodiment, examples of inorganic salts of amines are
bisulfates, borates, bromides, chlorides, hemisulfates,
hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates
(hydroxyethanesulfonates), iodates, iodides, isothionates, nitrate,
persulfates, phosphate, sulfates, sulfamates, sulfanilates,
sulfonic acids (alkylsulfonates, arylsulfonates, halogen
substituted alkylsulfonates, halogen substituted arylsulfonates),
sulfonates and thiocyanates.
In one embodiment, examples of organic salts of amines comprise
aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,
carboxylic and sulfonic classes of organic acids, examples of which
are acetates, arginines, aspartates, ascorbates, adipates,
anthranilate, algenate, alkane carboxylates, substituted alkane
carboxylates, alginates, to benzenesulfonates, benzoates,
bisulfates, butyrates, bicarbonates, bitartrates, carboxilates,
citrates, camphorates, camphorsulfonates, cyclohexylsulfamates,
cyclopentanepropionates, calcium edetates, camsylates, carbonates,
clavulanates, cinnamates, dicarboxylates, digluconates,
dodecylsulfonates, dihydrochlorides, decanoates, enanthuates,
ethanesulfonates, edetates, edisylates, estolates, esylates,
fumarates, formates, fluorides, galacturonates, gluconates,
glutamates, glycolates, glucorate, glucoheptanoates,
glycerophosphates, gluceptates, glycollylarsanilates, glutarates,
glutamate, heptanoates, hexanoates, hydroxymaleates,
hydroxycarboxlic acids, hexylresorcinates, hydroxybenzoates,
hydroxynaphthoate, hydrofluorate, lactates, lactobionates,
laurates, malates, maleates, methylenebis(beta-oxynaphthoate),
malonates, mandelates, mesylates, methane sulfonates,
methylbromides, methylnitrates, methylsulfonates, monopotassium
maleates, mucates, monocarboxylates, mitrates,
naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates,
napsylates, N-methylglucamines, oxalates, octanoates, oleates,
pamoates, phenylacetates, picrates, phenylbenzoates, pivalates,
propionates, phthalates, phenylacetate, pectinates,
phenylpropionates, palmitates, pantothenates, polygalacturates,
pyruvates, quinates, salicylates, succinates, stearates,
sulfanilate, subacetates, tartarates, theophyllineacetates,
p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates,
tannates, teoclates, trihaloacetates, triethiodide,
tricarboxylates, undecanoates or valerates.
In one embodiment, examples of inorganic salts of carboxylic acids
or phenols comprise ammonium, alkali metals to include lithium,
sodium, potassium, cesium; alkaline earth metals to include
calcium, magnesium, aluminium; zinc, barium, cholines or quaternary
ammoniums.
In another embodiment, examples of organic salts of carboxylic
acids or phenols comprise arginine, organic amines to include
aliphatic organic amines, alicyclic organic amines, aromatic
organic amines, benzathines, t-butylamines, benethamines
(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,
diethanolamines, ethanolamines, ethylenediamines, hydrabamines,
imidazoles, lysines, methylamines, meglamines,
N-methyl-D-glucamines, N,N'-dibenzylethylenediamines,
nicotinamides, organic amines, ornithines, pyridines, picolinates,
piperazines, procain, tris(hydroxymethyl)methylamines,
triethylamines, triethanolamines, trimethylamines, tromethamines or
ureas.
In one embodiment, the salts may be formed by conventional means,
such as by reacting the free base or free acid form of the product
with one or more equivalents of the appropriate acid or base in a
solvent or medium in which the salt is insoluble or in a solvent
such as water, which is removed in vacuo or by freeze drying or by
exchanging the ions of a existing salt for another ion or suitable
ion-exchange resin.
In one embodiment, the invention also includes N-oxides of the
amino substituents of the compounds described herein. Also, esters
of the phenolic compounds can be made with aliphatic and aromatic
carboxylic acids, for example, acetic acid and benzoic acid
esters.
This invention further includes a process for preparing derivatives
of the SARM compounds. In some embodiments, the term "derivative"
includes, but is not limited to, ether derivatives, acid
derivatives, amide derivatives, ester derivatives and the like.
Methods of preparing derivatives are known to a person skilled in
the art. For example, ether derivatives are prepared by coupling of
the corresponding alcohols. Amide and ester derivatives are
prepared from the corresponding carboxylic acid by a reaction with
amines and alcohols, respectively.
In some embodiments, this invention comprises a process for
preparing hydrates of the SARM compounds. In one embodiment the
term "hydrate" includes, but is not limited to, hemi-hydrate,
monohydrate, dihydrate, trihydrate and the like. Hydrates of the
SARM compounds may be prepared by contacting the SARM compound with
water under suitable conditions to produce the hydrate of choice.
The term "hemi-hydrate" refers to hydrate in which the molecular
ratio of water molecules to anhydrous compound is 1:2.
This invention further includes a process for preparing
pharmaceutical products of the SARM compounds. The term
"pharmaceutical product" means a composition suitable for
pharmaceutical use (pharmaceutical composition), as defined
herein.
In some embodiments, this invention comprises a process for
preparing analogs of the SARM compounds. In one embodiment the term
"analog" refers to a compound with a structure, which is similar,
but not identical to that of the referenced compound. In another
embodiment the term "analog" refers to an isomer or derivative of
the SARM compound. In another embodiment the term "analog of a SARM
compound" of this invention refers to a compound having different
substituents on each or both phenyl rings in the compound. In
another embodiment, the term "analog" refers to the incorporation
of different aromatic rings, for example pyridyl rings, in place of
the one or both benzene rings. In another embodiment, the term
"analog" refers to the incorporation of a sulfur atom instead of
each or to both ether and keto groups.
In some embodiments, this invention comprises a metabolite of the
SARM compounds. The term "metabolite" refers, in some embodiments
to any substance produced from another substance by mimicking or
via metabolic process. In some embodiment such metabolites can be
prepared synthetically and are active in situ, as they are
comparable to naturally produced metabolites.
In some embodiments, the term "about" refers to an up to 10%
variance from a specified value, or in some embodiments, an up to
5% variance from a specified value, or in some embodiments, an up
to 1% variance from a specified value. In some embodiments, the
term "about" refers to a value falling within a scientifically
acceptable error range for that type of value, which will depend on
the qualitative nature of the measurement obtained given the tools
and methodology available.
In some embodiments, the term "unique" as used herein refers to
being the only one, or in some embodiments, the term "unique"
refers to being without a like or equal.
Pharmaceutical Compositions
In one embodiment, this invention provides a composition comprising
a crystalline form of anhydrous (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and a suitable carrier or diluent.
In another embodiment, this invention provides a composition
comprising a crystalline form A of anhydrous
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and a suitable carrier or diluent.
In one embodiment, this invention provides a composition comprising
a paracrystalline form of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and a suitable carrier or diluent.
In one embodiment, this invention provides a composition comprising
a paracrystalline form B' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide and a suitable carrier or diluent.
In one embodiment, this invention provides a composition comprising
a mixture of any solid forms of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound of this invention and a suitable carrier
or diluent.
In another embodiment, this invention provides a composition
comprising a mixture of crystalline and paracrystalline solid forms
of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound and a suitable carrier or diluent.
In another embodiment, this invention provides a composition
comprising a mixture of crystalline form A and paracrystalline
solid form B' of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide compound and a suitable carrier or diluent.
In one embodiment, this invention encompasses compositions
comprising the different forms of (R) or
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide they can be in different ratios or a single form
per composition, which possesses properties useful in the treatment
of androgen-related conditions described herein. In another
embodiment, this invention encompasses compositions comprising
different isomers of
N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-meth-
ylpropanamide, they can be in different ratios or a single isomer
per composition, which possesses properties useful in the treatment
of androgen-related conditions described herein.
In some embodiments, the phrase, "pharmaceutical composition"
refers to a "therapeutically effective amount" of the active
ingredient, i.e. the SARM compound, together with a
pharmaceutically acceptable carrier or diluent. In some
embodiments, the phrase "therapeutically effective amount" refers
to an amount which provides a therapeutic effect for a given
condition and administration regimen.
The pharmaceutical compositions containing the SARM agent can be
administered to a subject by any method known to a person skilled
in the art, such as parenterally, paracancerally, transmucosally,
transdermally, intramuscularly, intravenously, intradermally,
subcutaneously, intraperitoneally, intraventricularly,
intracranially or intratumorally.
In another embodiment this invention provides, a composition of the
solid forms of this invention and a suitable carrier or
diluent.
In one embodiment, the pharmaceutical compositions are administered
orally, and are thus formulated in a form suitable for oral
administration, i.e. as a solid preparation. Suitable solid oral
formulations include tablets, capsules, pills, granules, pellets
and the like. In one embodiment of the present invention, the SARM
compounds are formulated in a capsule. In accordance with this
embodiment, the compositions of the present invention to comprise
in addition to the SARM active compound and the inert carrier or
diluent, a hard gelating capsule.
Oral formulations containing the present polymorph can comprise any
conventionally used oral forms, including tablets, capsules, buccal
forms, troches, or lozenges. Capsules may contain mixtures of the
crystalline form A in the desired percentage together any other
polymorph(s) of SARM or amorphous SARM. Capsules or tablets of the
desired crystalline form of the desired percentage composition may
also be combined with mixtures of other active compounds or inert
fillers and/or diluents such as the pharmaceutically acceptable
starches (e.g. corn, potato or tapioca starch), sugars, artificial
sweetening agents, powdered celluloses, such as crystalline and
microcrystalline celluloses, flours, gelatins, gums, etc.
Tablet formulations can be made by conventional compression, wet
granulation, or dry granulation methods and utilize
pharmaceutically acceptable diluents (fillers), binding agents,
lubricants, disintegrants, suspending or stabilizing agents,
including, but not limited to, magnesium stearate, stearic acid,
talc, sodium lauryl sulfate, microcrystalline cellulose,
carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin,
alginic acid, acacia gum, xanthan gum, sodium citrate, complex
silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol,
dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol,
sodium chloride, talc, dry starches and powdered sugar. Oral
formulations, in some embodiments, utilize standard delay or time
release formulations or spansules.
Example excipient systems suitable for preparing formulations of
the present polymorph include one or more fillers, disintegrants,
and lubricants.
The filler component can be any filler component known in the art
including, but not limited to, lactose, microcrystalline cellulose,
sucrose, mannitol, calcium phosphate, calcium carbonate, powdered
cellulose, maltodextrin, sorbitol, starch, or xylitol.
Disintegrants suitable for use in the present formulations can be
selected from those known in the art, including pregelatinized
starch and sodium starch glycolate. Other useful disintegrants
include croscarmellose sodium, crospovidone, starch, alginic acid,
sodium alginate, clays (e.g. veegum or xanthan gum), cellulose
floc, ion exchange resins, or effervescent systems, such as those
utilizing food acids (such as citric acid, tartaric acid, malic
acid, fumaric acid, lactic acid, adipic acid, ascorbic acid,
aspartic acid, erythorbic acid, glutamic acid, and succinic acid)
and an alkaline carbonate component (such as sodium bicarbonate,
calcium carbonate, magnesium carbonate, potassium carbonate,
ammonium carbonate, etc.). The disintegrant(s) useful herein can
comprise from about 4% to about 40% of the composition by weight,
preferably from about 15% to about 35%, more preferably from about
20% to about 35%.
The pharmaceutical formulations can also contain an antioxidant or
a mixture of antioxidants, such as ascorbic acid. Other
antioxidants which can be used include sodium ascorbate and
ascorbyl palmitate, preferably in conjunction with an amount of
ascorbic acid. An example range for the antioxidant(s) is from
about 0.5% to about 15% by weight, most preferably from about 0.5%
to about 5% by weight.
In some embodiments of this invention, the active pharmacological
agent(s) comprise from about 0.5% to about 20%, by weight, of the
final composition, or in some embodiments, from about 1% to about
5%, and the coating or capsule comprises up to about 8%, by weight,
of the final composition.
The formulations described herein can be used in an uncoated or
non-encapsulated solid form. In some embodiments, the
pharmacological compositions are optionally coated with a film
coating, for example, comprising from about 0.3% to about 8% by
weight of the overall composition. Film coatings useful with the
present formulations are known in the art and generally consist of
a polymer (usually a cellulosic type of polymer), a colorant and a
plasticizer. Additional ingredients such as wetting agents, sugars,
flavors, oils and lubricants may be included in film coating
formulations to impart certain characteristics to the film coat.
The compositions and formulations herein may also be combined and
processed as a solid, then placed in a capsule form, such as a
gelatin capsule.
In another embodiment, the active compound can be delivered in a
vesicle, in particular a liposome (see Langer, Science
249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of
Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.),
Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp.
317-327; see generally ibid).
As used herein "pharmaceutically acceptable carriers or diluents"
are well known to those skilled in the art. The carrier or diluent
may be a solid carrier or diluent for solid formulations.
Solid carriers/diluents include, but are not limited to, a gum, a
starch (e.g. corn starch, pregeletanized starch), a sugar (e.g.,
lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g.
microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),
calcium carbonate, magnesium oxide, talc, or mixtures thereof.
In addition, the compositions may further comprise binders (e.g.
acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),
disintegrating agents (e.g. cornstarch, potato starch, alginic
acid, silicon dioxide, croscarmelose sodium, crospovidone, guar
gum, sodium starch glycolate), buffers (e.g., Tris-HCl, acetate,
phosphate) of various pH and ionic strength, additives such as
albumin or gelatin to prevent absorption to surfaces, detergents
(e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease
inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation
enhancers, solubilizing agents (e.g., glycerol, polyethylene
glycerol), anti-oxidants (e.g., ascorbic acid, sodium
metabisulfite, butylated hydroxyanisole), stabilizers (e.g.
hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity
increasing agents (e.g. carbomer, colloidal silicon dioxide, ethyl
cellulose, guar gum), sweetners (e.g. aspartame, citric acid),
preservatives (e.g., Thimerosal, benzyl alcohol, parabens),
lubricants (e.g. stearic acid, magnesium stearate, polyethylene
glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon
dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate),
emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl
sulfate), polymer coatings (e.g., poloxamers or poloxamines),
coating and film forming agents (e.g. ethyl cellulose, acrylates,
polymethacrylates) and/or adjuvants.
In one embodiment, the pharmaceutical compositions provided herein
are controlled release compositions, i.e. compositions in which the
SARM compound is released over a period of time after
administration. In another embodiment, the composition is an
immediate release composition, i.e. a composition in which all of
the SARM compound is released immediately after administration.
In yet another embodiment, the pharmaceutical composition can be
delivered in a controlled release system. For example, the agent
may be administered using liposomes, or other modes of oral
administration.
The compositions may also include incorporation of the active
material into or onto particulate preparations of polymeric
compounds such as polylactic acid, polglycolic acid, hydrogels,
etc, or onto liposomes, microemulsions, micelles, unilamellar or
multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such
compositions will influence the physical state, solubility,
stability, rate of in vivo release, and rate of in vivo
clearance.
The preparation of pharmaceutical compositions which contain an
active component is well understood in the art, for example by
mixing, granulating, or tablet-forming processes. The active
therapeutic ingredient is often mixed with excipients which are
pharmaceutically acceptable and compatible with the active
ingredient. For oral administration, the SARM agents or their
physiologically tolerated derivatives such as salts, esters,
N-oxides, and the like are mixed with additives customary for this
purpose, such as vehicles, stabilizers, or inert diluents, and
converted by customary methods into suitable forms for
administration, such as tablets, coated tablets, hard or soft
gelatin capsules, aqueous, alcoholic or oily solutions.
An active component can be formulated into the composition as
neutralized pharmaceutically acceptable salt forms.
Pharmaceutically acceptable salts include the acid addition salts
(formed with the free amino groups of the polypeptide or antibody
molecule), which are formed with inorganic acids such as, for
example, hydrochloric or phosphoric acids, or such organic acids as
acetic, oxalic, tartaric, mandelic, and the like. Salts formed from
the free carboxyl groups can also be derived from inorganic bases
such as, for example, sodium, potassium, ammonium, calcium, or
ferric hydroxides, and such organic bases as isopropylamine,
trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the
like.
For use in medicine, the salts of the SARM will be pharmaceutically
acceptable salts. Other salts may, however, be useful in the
preparation of the compounds according to the invention or of their
pharmaceutically acceptable salts. Suitable pharmaceutically
acceptable salts of the compounds of this invention include acid
addition salts which may, for example, be formed by mixing a
solution of the compound according to the invention with a solution
of a pharmaceutically acceptable acid such as hydrochloric acid,
sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid,
succinic acid, acetic acid, benzoic: acid, oxalic acid, citric
acid, tartaric acid, carbonic acid or phosphoric acid.
Biological Activity of Selective Androgen Modulator Compounds
The solid forms and processes for producing the same provided
herein are, in some embodiments, directed to selective androgen
receptor modulators (SARMs), which are useful for oral testosterone
replacement therapy, having unexpected in-vivo androgenic and
anabolic activity. In some embodiments, appropriately substituted
compounds are effective to treat prostate cancer and useful for
imaging of prostate cancer.
As contemplated herein, the appropriately substituted SARM
compounds of the present invention are useful for a) male
contraception; b) treatment of a variety of hormone-related
conditions, for example conditions associated with Androgen Decline
in Aging Male (ADAM), such as fatigue, depression, decreased
libido, sexual dysfunction, erectile dysfunction, hypogonadism,
osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia,
osteoporosis, benign prostate hyperplasia, alterations in mood and
cognition and prostate cancer; c) treatment of conditions
associated with ADIF, such as sexual dysfunction, decreased sexual
libido, hypogonadism, sarcopenia, osteopenia, osteoporosis,
alterations in cognition and mood, depression, anemia, hair loss,
obesity, endometriosis, breast cancer, uterine cancer and ovarian
cancer; d) treatment and/or prevention of chronic muscular wasting;
e) decreasing the incidence of, halting or causing a regression of
prostate cancer; f) oral androgen relacement and/or other clinical
therapeutic and/or diagnostic areas.
As used herein, receptors for extracellular signaling molecules are
collectively referred to as "cell signaling receptors". Many cell
signaling receptors are transmembrane proteins on a cell surface;
when they bind an extracellular signaling molecule (i.e., a
ligand), they become activated so as to generate a cascade of
intracellular signals that alter the behavior of the cell. In
contrast, in some cases, the receptors are inside the cell and the
signaling ligand has to enter the cell to activate them; these
signaling molecules therefore must be sufficiently small and
hydrophobic to diffuse across the plasma membrane of the cell. As
used herein, these receptors are collectively referred to as
"intracellular cell signaling receptors".
Steroid hormones are one example of small hydrophobic molecules
that diffuse directly across the plasma membrane of target cells
and bind to intracellular cell signaling receptors. These receptors
are structurally related and constitute the intracellular receptor
superfamily (or steroid-hormone receptor superfamily). Steroid
hormone receptors include progesterone receptors, estrogen
receptors, androgen receptors, glucocorticoid receptors, and
mineralocorticoid receptors. The present invention is particularly
directed to androgen receptors.
In addition to ligand binding to the receptors, the receptors can
be blocked to prevent ligand binding. When a substance binds to a
receptor, the three-dimensional structure of the substance fits
into a space created by the three-dimensional structure of the
receptor in a ball and socket configuration.
In one embodiment, the present invention is directed to processes
for preparing solid forms of selective androgen receptor modulator
compounds which are agonist compounds. Thus, in one embodiment, the
SARM compounds of the present invention are useful in to binding to
and activating steroidal hormone receptors. In one embodiment, the
agonist compound of the present invention is an agonist which binds
the androgen receptor. In another embodiment, the compound has high
affinity for the androgen receptor. In another embodiment, the
agonist compound also has anabolic activity. In another embodiment,
the present invention provides selective androgen modulator
compounds which have agonistic and anabolic activity of a
nonsteroidal compound for the androgen receptor.
In one embodiment, the present invention is directed to processes
for preparing solid forms of selective androgen receptor modulator
compounds which are antagonist compounds. Thus, in one embodiment,
the solid forms of the SARM compounds of the present invention are
useful in binding to and inactivating steroidal hormone receptors.
In another embodiment, the solid forms of the invention have a high
affinity for the androgen receptor. In another embodiment, the
solid forms of this invention also have anabolic activity. In
another embodiment, the solid forms of the SARM compounds bind
irreversibly to the androgen receptor. In another embodiment, the
solid forms of the SARM compounds are alkylating agents.
In yet another embodiment, the solid forms of the SARM compounds of
the present invention can be classified as partial AR
agonist/antagonists. The solid forms of the SARMs are AR agonists
in some tissues, and cause increased transcription of AR-responsive
genes (e.g. muscle anabolic effect). In other tissues, these
compounds serve as inhibitors at the AR to prevent agonistic
effects of the native androgens.
Assays to determine whether the compounds of the present invention
are AR agonists or antagonists are well known to a person skilled
in the art. For example, AR agonistic activity can be determined by
monitoring the ability of the solid forms of the SARM compounds to
maintain and/or stimulate the growth of AR containing tissue such
as prostate and seminal vesicles, as measured by weight. AR
antagonistic activity can be determined by monitoring the ability
of the SARM compounds to inhibit the growth of AR containing
tissue.
In another embodiment, the solid forms of the SARM compounds bind
irreversibly to the androgen receptor of a mammal, for example a
human. Thus, in one embodiment, the compounds of the present
invention may contain a functional group (e.g. affinity label) that
allows alkylation of the androgen receptor (i.e. covalent bond
formation). Thus, in this case, the compounds are alkylating agents
which bind irreversibly to the receptor and, accordingly, cannot be
displaced by a steroid, such as the endogenous ligands DHT and
testosterone. An to "alkylating agent" is defined herein as an
agent which alkylates (forms a covalent bond) with a cellular
component, such as DNA, RNA or protein. It is a highly reactive
chemical that introduces alkyl radicals into biologically active
molecules and thereby prevents their proper functioning. The
alkylating moiety is an electrophilic group that interacts with
nucleophilic moieties in cellular components.
According to one embodiment of the present invention, a method is
provided for binding the solid forms of the SARM compounds of the
present invention to an androgen receptor by contacting the
receptor with the solid forms of the SARM compound, such as
polymorph form A, polymorph form C, polymorph form D,
paracrystalline form B', paracrystalline B'', a solvate thereof, a
polymorph thereof, a metabolite thereof, etc., or any combination
thereof, under conditions effective to cause the selective androgen
receptor modulator compound to bind the androgen receptor. The
binding of the solid forms of the selective androgen receptor
modulator compounds to the androgen receptor enables the compounds
of the present invention to be useful as a male contraceptive and
in a number of hormone therapies. The agonist compounds bind to and
activate the androgen receptor. The antagonist compounds bind to
and inactivate the androgen receptor. Binding of the agonist or
antagonist compounds is either reversible or irreversible.
In one embodiment, the solid forms of the SARM compounds of the
present invention are administered as the sole active ingredient.
However, also encompassed within the scope of the present invention
are methods for hormone therapy, for treating prostate cancer, for
delaying the progression of prostate cancer, and for preventing
and/or treating the recurrence of prostate cancer, which comprise
administering the solid forms of the SARM compounds in combination
with one or more therapeutic agents. These agents include, but are
not limited to: LHRH analogs, reversible antiandrogens,
antiestrogens, anticancer drugs, 5-alpha reductase inhibitors,
aromatase inhibitors, progestins, agents acting through other
nuclear hormone receptors, selective estrogen receptor modulators
(SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine,
bisphosphonate, and one or more solid forms of the SARMS, for
example one with AR agonistic activity.
Thus, in one embodiment, the present invention provides
compositions and pharmaceutical compositions comprising the solid
forms of the selective androgen receptor modulator compound, in
combination with an LHRH analog. In another embodiment, the present
invention provides compositions and pharmaceutical compositions
comprising the solid forms of the selective androgen receptor
modulator compound, in combination with a to reversible
antiandrogen. In another embodiment, the present invention provides
compositions and pharmaceutical compositions comprising the solid
forms of the selective androgen receptor modulator compound, in
combination with an antiestrogen. In another embodiment, the
present invention provides compositions and pharmaceutical
compositions comprising the solid forms of the selective androgen
receptor modulator compound, in combination with an anticancer
drug. In another embodiment, the present invention provides
compositions and pharmaceutical compositions comprising the solid
forms of the selective androgen receptor modulator compound, in
combination with a 5-alpha reductase inhibitor. In another
embodiment, the present invention provides compositions and
pharmaceutical compositions comprising the solid forms of the
selective androgen receptor modulator compound, in combination with
an aromatase inhibitor. In another embodiment, the present
invention provides compositions and pharmaceutical compositions
comprising the solid forms of the selective androgen receptor
modulator compound, in combination with a progestin. In another
embodiment, the present invention provides compositions and
pharmaceutical compositions comprising the solid forms of the
selective androgen receptor modulator compound, in combination with
an agent acting through other nuclear hormone receptors. In another
embodiment, the present invention provides compositions and
pharmaceutical compositions comprising the solid forms of the
selective androgen receptor modulator compound, in combination with
a selective estrogen receptor modulators (SERM). In another
embodiment, the present invention provides compositions and
pharmaceutical compositions comprising the solid forms of the
selective androgen receptor modulator compound, in combination with
progesterone. In another embodiment, the present invention provides
compositions and pharmaceutical compositions comprising the solid
forms of the selective androgen receptor modulator compound, in
combination with estrogen. In another embodiment, the present
invention provides compositions and pharmaceutical compositions
comprising the solid forms of the selective androgen receptor
modulator compound, in combination with PDE5 inhibitors. In another
embodiment, the present invention provides compositions and
pharmaceutical compositions comprising the solid forms of the
selective androgen receptor modulator compound, in combination with
apomorphine. In another embodiment, the present invention provides
compositions and pharmaceutical compositions comprising the solid
forms of the selective androgen receptor modulator compound, in
combination with a bisphosphonate. In another embodiment, the
present invention provides compositions and pharmaceutical
compositions comprising the solid forms of the selective androgen
receptor modulator compound, in combination with one or more
additional SARMs.
The following examples are presented in order to more fully
illustrate the preferred embodiments of the invention. They should
in no way be construed, however, as limiting the broad scope of the
invention.
EXPERIMENTAL DETAILS SECTION
Example 1
Synthesis of Compound S-1
(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid. D-Proline, 14.93
g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an
ice bath; the resulting alkaline solution was diluted with acetone
(71 mL). An acetone solution (71 mL) of methacrylolyl chloride
(13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were
simultaneously added over 40 min to the aqueous solution of
D-proline in an ice bath. The pH of the mixture was kept at
10-11.degree. C. during the addition of the methacrylolyl chloride.
After stirring (3 h, room temperature), the mixture was evaporated
in vacuo at a temperature at 35-45.degree. C. to remove acetone.
The resulting solution was washed with ethyl ether and was
acidified to pH 2 with concentrated HCl. The acidic mixture was
saturated with NaCl and was extracted with EtOAc (100 mL.times.3).
The combined extracts were dried over Na.sub.2SO.sub.4, filtered
through Celite, and evaporated in vacuo to give the crude product
as a colorless oil. Recrystallization of the oil from ethyl ether
and hexanes afforded 16.2 (68%) of the desired compound as
colorless crystals: mp 102-103.degree. C. (lit. [214] mp
102.5-103.5.degree. C.); the NMR spectrum of this compound
demonstrated the existence of two rotamers of the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.28 (s) and 5.15 (s)
for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer
(totally 2H for both rotamers, vinyl CH.sub.2), 4.48-4.44 for the
first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for
both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H,
CH.sub.2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH.sub.2, CH, Me);
.sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. for major rotamer
173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor
rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7;
IR (KBr) 3437 (OH), 1737 (C.dbd.O), 1647 (CO, COOH), 1584, 1508,
1459, 1369, 1348, 1178 cm.sup.-1;
[.alpha.].sub.D.sup.26+80.8.degree. (c=1, MeOH); Anal. Calcd. for
C.sub.9H.sub.13NO.sub.3: C 59.00, H 7.15, N 7.65. Found: C 59.13, H
7.19, N 7.61.
##STR00027##
(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-
-dione. A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was
added dropwise to a stirred solution of the
(methyl-acryloyl)-pyrrolidine (16.1 g, 88 mmol) in 70 mL of DMF
under argon at room temperature, and the resulting mixture was
stirred 3 days. The solvent was removed in vacuo, and a yellow
solid was precipitated. The solid was suspended in water, stirred
overnight at room temperature, filtered, and dried to give 18.6
(81%) (smaller weight when dried .about.34%) of the title compound
as a yellow solid: mp 152-154.degree. C. (lit. [214] mp
107-109.degree. C. for the S-isomer); .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH at the
chiral center), 4.02 (d, J=11.4 Hz, 1H, CHH.sub.a), 3.86 (d, J=11.4
Hz, 1H, CHH.sub.b), 3.53-3.24 (m, 4H, CH.sub.2), 2.30-2.20 (m, 1H,
CH), 2.04-1.72 (m, 3H, CH.sub.2 and CH), 1.56 (s, 2H, Me); .sup.13C
NMR (75 MHz, DMSO-d.sub.6) .delta. 167.3, 163.1, 83.9, 57.2, 45.4,
37.8, 29.0, 22.9, 21.6; IR (KBr) 3474, 1745 (C.dbd.O), 1687
(C.dbd.O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm.sup.-1;
[.alpha.].sub.D.sup.26+124.5.degree. (c=1.3, chloroform); Anal.
Calcd. for C.sub.9H.sub.12BrNO.sub.3: C 41.24, H 4.61, N 5.34.
Found: C 41.46, H 4.64, N 5.32.
##STR00028##
(2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid. A mixture of
bromolactone (18.5 g, 71 mmol) in 300 mL of 24% HBr was heated at
reflux for 1 h. The resulting solution was diluted with brine (200
mL), and was extracted with ethyl acetate (100 mL.times.4). The
combined extracts were washed with saturated NaHCO.sub.3 (100
mL.times.4). The aqueous solution was acidified with concentrated
HCl to pH=1, which, in turn, was extracted with ethyl acetate (100
mL.times.4). The combined organic solution was dried over
Na.sub.2SO.sub.4, filtered through Celite, and evaporated in vacuo
to dryness. Recrystallization from toluene afforded 10.2 g (86%) of
the desired compound as colorless crystals: mp 107-109.degree. C.
(lit. [214] mp 109-113.degree. C. for the S-isomer); .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 3.63 (d, J=10.1 Hz, 1H, CHH.sub.a),
3.52 (d, J=10.1 Hz, 1H, CHH.sub.b), 1.35 (s, 3H, Me); IR (KBr) 3434
(OH), 3300-2500 (COOH), 1730 (C.dbd.O), 1449, 1421, 1380, 1292,
1193, 1085 cm.sup.-1; [.alpha.].sub.D.sup.26+10.50 (c=2.6, to
MeOH); Anal. Calcd. for C.sub.4H.sub.7BrO.sub.3: C 26.25; H, 3.86.
Found: C 26.28, H 3.75.
##STR00029##
Synthesis of
(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylprop-
anamide. Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to
a cooled solution (less than 4'C) of 6 (51.13 g, 0.28 mol) in 300
mL of THF under an argon atmosphere. The resulting mixture was
stirred for 3 h under the same condition. To this was added
Et.sub.3N (39.14 g, 0.39 mol) and stirred for 20 min under the same
condition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0 g,
0.21 mol), 400 mL of THF were added and then the mixture was
allowed to stir overnight at room temperature. The solvent was
removed under reduced pressure to give a solid which was treated
with 300 mL of H.sub.2O, extracted with EtOAc (2.times.400 mL). The
combined organic extracts were washed with saturated NaHCO.sub.3
solution (2.times.300 mL) and brine (300 mL). The organic layer was
dried over MgSO.sub.4 and concentrated under reduced pressure to
give a solid which was purified from column chromatography using
CH.sub.2Cl.sub.2/EtOAc (80:20) to give a solid. This solid was
recrystallized from CH.sub.2Cl.sub.2/hexane to give 55.8 g (73.9%)
of
(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylprop-
anamide as a light-yellow solid.
.sup.1H NMR (CDCl.sub.3/TMS) .delta. 1.66 (s, 3H, CH.sub.3), 3.11
(s, 1H, OH), 3.63 (d, J=10.8 Hz, 1H, CH.sub.2), 4.05 (d, J=10.8 Hz,
1H, CH.sub.2), 7.85 (d, J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1, 8.4
Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH).
Calculated Mass: 349.99, [M-H].sup.- 349.0. M.p.: 124-126.degree.
C.
##STR00030##
Synthesis of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide. A mixture of bromoamide
((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpro-
panamide, 50 g, 0.14 mol), anhydrous K.sub.2CO.sub.3 (59.04 g, 0.43
mol), and 4-cyanophenol (25.44 g, 0.21 mol) in 500 mL of 2-propanol
was heated to reflux for 3 h and then concentrated under reduced
pressure to give a solid. The resulting residue was treated with
500 mL of H.sub.2O and then extracted with EtOAc (2.times.300 mL).
The combined EtOAc extracts were washed with 10% NaOH (4.times.200
mL) and brine. The organic layer was dried over MgSO.sub.4 and then
concentrated under reduced pressure to give an oil which was
treated with 300 mL of ethanol and an activated carbon. The
reaction mixture was heated to reflux for 1 h and then the hot
mixture was filtered through Celite. The filtrate was concentrated
under reduced pressure to give an oil. This oil was purified by
column chromatography using CH.sub.2Cl.sub.2/EtOAc (80:20) to give
an oil which was crystallized from CH.sub.2Cl.sub.2/hexane to give
33.2 g (59.9%) of
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2--
methylpropanamide as a colorless solid (a cotton type).
.sup.1H NMR (CDCl.sub.3/TMS) .delta. 1.63 (s, 3H, CH.sub.3), 3.35
(s, 1H, OH), 4.07 (d, J=9.04 Hz, 1H, CH), 4.51 (d, J=9.04 Hz, 1H,
CH), 6.97-6.99 (m, 2H, ArH), 7.57-7.60 (m, 2H, ArH), 7.81 (d,
J=8.55 Hz, 1H, ArH), 7.97 (dd, J=1.95, 8.55 Hz, 1H, ArH), 8.12 (d,
J=1.95 Hz, 1H, ArH), 9.13 (bs, 1H, NH). Calculated Mass: 389.10,
[M-H].sup..about.388.1. Mp: 92-94.degree. C.
Example 2
Crystallization of S-1 SARM Compound
Materials and Methods
Methods:
X-Ray Powder Diffraction (XRPD)
XRPD was used for the determination of the crystal structure or
recognition of liquid crystals materials in partially crystalline
mixtures. XRPD was performed with PANalytical X-ray diffractometer
PW 1710, where the tube anode was Cu with Ka radiation. The pattern
was collected in step scan mode (step size of 0.02
.degree.2.theta., counting time 2.4 s/step. The sample was measured
without any special treatment other than the application of slight
pressure to get a flat surface. The measurements were performed at
an ambient air atmosphere.
Raman Spectroscopy
FT-Raman spectra were recorded on a Bruker RFS 100 FT-Raman system
with a near infrared Nd:YAG laser operating at 1064 nm and a liquid
nitrogen-cooled germanium detector. For each sample, 64 scans with
a resolution of 2 cm.sup.-1 were accumulated. The laser power used
was at 100 mW. Raman measurements were conducted using aluminum
sample holders or hermetically closed glass tubes at room
temperature.
Thermo Gravimetric-Fourier Transform Infrared (TG-FTIR) and Thermo
Gravimetric Analysis
The TG-FTIR instrument consists of a thermogravimetric analyzer
(TG) coupled with a Fourier-Transform Infrared (FTIR) spectrometer
for the analysis of evolved gases such as gases of H.sub.2O, by
their mass loss combined with characterization of the evolved
components. Thermo gravimetric measurements were carried out with a
Netzsch Thermo-Microbalance TG 209 coupled to a Bruker FTIR
Spectrometer Vector 22. Sample pans with a pinhole were used under
an N.sub.2 atmosphere, at a heating rate of 10 K/min, with a
temperature range of 25 to 250.degree. C. Additional Thermo
Gravimetric Analysis was conducted using a TA Instruments Q500 TGA
under various conditions.
Differential Scanning Calorimetry (DSC)
Thermal analysis was carried out with a Perkin Elmer DSC7 with the
following experimental conditions: 3 to 6 mg sample mass, closed
gold sample pan, temperature range -50.degree. C. to 120.degree.
C., heating rate 20 K/min The samples were weighed in air or dry
N.sub.2 atmosphere. Additional thermal analysis was conducted using
a TA Instruments Q1000 DSC using hermetic aluminum pans under
various conditions.
Dynamic Vapor Sorption (DVS)
Dynamic vapor sorption quantification relates the mass of water
absorbed and subsequently desorbed during the crystallization
process. In order to define whether batch P1, P2 and P4 are
hydrated polymorphs, DVS measurements were conducted (FIG. 9). A
sample (13 to 14 mg) was placed on a Pt pan, and the sample was
allowed to equilibrate at 25.degree. C./50% r.h. before starting a
pre-defined humidity program (1.0 hours 50%, from 50% r.h. to 95%
r.h.: 5% r.h./hour, 10 hours at 95% r.h., from 95% r.h. to 0% r.h.:
5% r.h./hour, 10 hours at 0% r.h., from 0 r.h. to 50% r.h.: 5%
r.h./hour, 1 hours at 50% r.h.
Scanning Electron Spectroscopy (SEM)
Images of S-1 batch P1, P2 and P4 (FIG. 8) were taken with an SEM
CamScan CS24 system.
Filtration
During the following experiments: suspension equilibration,
precipitation experiment, recrystallization, relative stability
experiments and water solubility experiment, a filtration step was
conducted. Centrifugal filter devices: Ultrafree-CL (0.22 la,m),
Millipore; Centrifuge type or Eppendorf 5804R were used at a
temperature of 22.degree. C. and centrifugation program of 2 min
3000 rpm.
High Performance Liquid Chromatography (HPLC)
HPLC was used to analyse the purity of S-1. HP 1090M HPLC machine
was used with the following conditions: Column: Symmetry Shield
RP18, 3.9.times.150 mm, 5 .mu.m Column temperature: 35.degree. C.
Injection volume: 10 .mu.L Solvent: acetonitrile+water 1:1 v/v
Mobile phase A: 0.1% TFA--water Mobile phase B: 0.1%
TFA--acetonitrile Flow rate: 1 mL/min Detection: UV at 271 nm Run
time: 21 min Retention time (S-1): 10.7 min Materials: Solvents
For all experiments, Fluka or Merck grade solvents were used.
Water: deionized (Fluka No. 95305)
Chemicals
Compound S-1 was synthesized as described in Example 1.
Results:
Four batches of S-1 compound designated accordingly, (S-1-P1),
(S-1-P2), (S-1-P3), and (S-1-P4) were selected for
characterization. S-1-P1, S-1-P2, and S-1-P3 were individual
batches prepared by the synthetic process described in Example 1.
Batch S-1-P4 was a sample of batch S-1-P1 exposed to 40 C/75% r.h.
during storage. The following experiments were conducted to
determine the stability, solubility and characteristics of
different solid forms of S-1 compound.
The following table presents the X-ray diffraction results of form
A of S-1 as depicted in FIG. 4A:
TABLE-US-00001 Angle d value Intensity Intensity 2-Theta .degree.
Angstrom Cps % % 5.56 15.9 2250 30 7.47 11.8 470 6 8.61 10.3 1399
19 9.93 8.9 3016 40 12.41 7.1 707 9 14.94 5.93 2647 35 16.66 5.32
6922 92 17.31 5.12 1049 14 18.03 4.92 397 5 18.52 4.79 930 12 19.25
4.61 830 11 19.83 4.47 823 11 20.63 4.30 740 10 21.80 4.07 988 13
22.33 3.98 7557 100 23.45 3.79 976 13 23.92 3.72 914 12 24.56 3.62
376 5 24.92 3.57 589 8 25.39 3.51 774 10 25.95 3.43 618 8 26.50
3.36 353 5 27.79 3.21 2123 28 28.80 3.10 734 10 29.68 3.01 410 5
30.07 2.97 656 9 30.49 2.93 423 6 31.42 2.84 391 5 32.49 2.75 330 4
33.66 2.66 431 6 34.78 2.58 444 6
The following table presents the X-ray diffraction results of form
A+C of S-1 as depicted in FIG. 12D, wherein the diffraction angles
of form C were identified:
TABLE-US-00002 Mixture Form A with Form C Peak Assignment Angle d
value Intensity Intensity not form A line 2-Theta .degree. Angstrom
Cps % 5.65 15.6 100 41 certain 6.89 12.8 7 3 7.43 11.9 8 3 8.68
10.2 42 17 probable 9.46 9.3 25 10 9.94 8.9 111 45 11.20 7.9 7 3
12.60 7.0 12 5 certain 13.49 6.6 9 4 14.89 5.95 82 33 15.17 5.84 22
9 Probable 15.99 5.54 41 17 16.84 5.26 164 67 17.21 5.15 64 26
18.00 4.92 17 7 18.54 4.78 45 18 19.37 4.58 27 11 19.86 4.47 39 16
20.66 4.29 21 9 21.79 4.08 46 19 22.36 3.97 246 100 certain 22.84
3.89 52 21 23.53 3.78 46 19 23.91 3.72 38 15 24.84 3.58 16 7 25.41
3.50 37 15 26.15 3.41 14 6 26.60 3.35 12 5 27.89 3.20 60 24 28.86
3.09 31 13 30.01 2.98 30 12 30.52 2.93 14 6 30.98 2.88 13 5 31.34
2.85 15 6 32.72 2.73 14 6 33.93 2.64 15 6 34.84 2.57 15 6
In one embodiment form C has additional lines which are overlaid by
signals of form A.
Peak search and d-value calculation were performed with software
EVA version 10, 0, 0, 0, Cu Kalpha2 was removed by software, and
only lines up to 35.degree. 2theta were listed.
The sample PP148-P1 was measured on a 0.1 mm sample holder on a
PANalytical PW1710 diffractometer.
The sample PP148-P52 was measured on a 0.1 mm sample holder on a
Bruker D8 Advance diffractometer.
The following table presents the X-ray diffraction results of form
D of S-1 as depicted in FIG. 18 (bottom):
TABLE-US-00003 Angle d value Intensity 2-Theta .degree. Angstrom
Cps I/Imax 4.42 19.99 17733 100.0 8.48 10.41 3026 17.1 8.80 10.04
1755 9.9 11.35 7.79 4598 25.9 11.76 7.52 805 4.5 12.72 6.96 1462
8.2 13.84 6.39 8635 48.7 14.45 6.13 5597 31.6 14.64 6.05 9445 53.3
15.10 5.86 7013 39.5 16.14 5.49 1644 9.3 16.64 5.32 1678 9.5 16.95
5.23 2357 13.3 17.41 5.09 484 2.7 17.59 5.04 678 3.8 18.04 4.91
2308 13.0 18.71 4.74 3439 19.4 19.04 4.66 1824 10.3 19.46 4.56 4093
23.1 20.48 4.33 989 5.6 20.84 4.26 7616 42.9 22.15 4.01 5058 28.5
22.78 3.90 1933 10.9 23.15 3.84 3851 21.7 23.47 3.79 2352 13.3
23.88 3.72 5583 31.5 24.74 3.60 10043 56.6 24.94 3.57 5395 30.4
25.29 3.52 3149 17.8 25.67 3.47 1290 7.3 26.14 3.41 692 3.9 26.46
3.37 1095 6.2 27.80 3.21 2402 13.5 28.32 3.15 1565 8.8 28.64 3.11
998 5.6 28.90 3.09 1212 6.8 29.38 3.04 3295 18.6 29.92 2.98 756 4.3
30.40 2.94 1278 7.2 31.19 2.87 851 4.8 31.86 2.81 1270 7.2 32.49
2.75 775 4.4 32.82 2.73 920 5.2 33.66 2.66 842 4.7 34.50 2.60 977
5.5 35.80 2.51 638 3.6 36.06 2.49 700 3.9 36.83 2.44 777 4.4 37.16
2.42 698 3.9 38.02 2.36 733 4.1 38.44 2.34 859 4.8 38.97 2.31 844
4.8 39.99 2.52 791 4.5 40.89 2.21 641 3.6 41.30 2.18 515 2.9
Water Vapor Sorption (Humidity Chamber)
The compound was stored in a glass tube under 96% r.h. (relative
humidity) in a humidity chamber at room temperature. After
different time of storage Raman measurements were conducted using
hermetically closed glass tubes. The results are summarized in
Table 1:
TABLE-US-00004 TABLE 1 Start- Concen- ing tration Form form Solvent
mg/ml Conditions produced A stored in humidified (powder) chamber
96% r.h./23.degree. C. 4 weeks A + small amount form B' 9 weeks A +
form B' 11 weeks A + approx. 20% form B' (see FIG. 17A) A water
111/5.0 23.degree. C. (suspension) sonication 5 min. (suspension)
stirred 19 h/37.degree. C. B' filtered & air dried (see FIG.
17B) A water + 5% 123/2.1 23.degree. C. (suspension) ethanol
stirred 3 h/83.degree. C. viscous sticky v/v mass cooled to
47.degree. C. within B' 1.5 h filtered & air dried A acetic
138/2.0 23.degree. C. (suspension) acid/water stirred 20
h/23.degree. C. A 1:2 v/v filtered & air dried (see FIG. 17C) A
water + 5% 105/2.0 23.degree. C. (suspension) acetic stirred 12
min/40.degree. C. (suspension) acid v/v sonicated 2 min.
(suspension) stirred 17 h/40.degree. C. viscous sticky cooled to
R.T. and mass B' removed solution
Measurement of the Approximate Solubility
To determine the approximate solubility at room temperature, the
solvent was added in steps to the solid material. After every
addition, the sample was well stirred. The addition of solvent was
continued until complete dissolution or until 15 ml of solvent was
added. The solubility of solid form A and B' at 23.degree. C. is
presented in Table 2.
TABLE-US-00005 TABLE 2 Solid Solubility Solvent form (mg/ml)
ethanol A >200 acetone A >200 TBME A >200 ethyl acetate A
>200 THF A >200 acetonitrile A >200 dichloromethane A
>200 1,4-dioxane A >200 acetic acid A >200 toluene A <6
turbid solution ethanol/water A >200 3:1 v/v ethanol/water A 50
1:1 v/v ethanol/water A <5 1:3 v/v ethanol/n-heptane A 180 1:1
v/v ethanol/n-heptane A 50 1:3 v/v acetone/n-heptane A >200 1:1
v/v acetone/n-heptane A 90 1:3 v/v THF/n-heptane A >200 1:1 v/v
THF/n-heptane A 65 1:3 v/v acetonitrile/ A >200 toluene 1:1 v/v
acetonitrile/ A 170 toluene 1:3 v/v ethyl acetate/ A 65 n-heptane
1:1 v/v ethyl acetate/ A 9 n-heptane 1:2 v/v ethyl acetate/ B'
>9 solid form n-heptane transformation into 1:2 v/v solid form A
ethyl acetate/ A 13 n-pentane 1:2 v/v ethyl formate/ A 12 n-pentane
1:2 v/v methyl acetate/ A 8 n-pentane 1:2 v/v ethyl acetate/ A
<5 turbid solution n-heptane 1:3 v/v
Suspension Equilibration Experiments
Suspension equilibration experiments were carried out with 81-128
mg of the compound. The suspensions were stirred with a magnetic
stirrer. The samples obtained after filtration were air dried at
ambient temperature for a short time only to prevent possible
desolvation of labile hydrates or solvates. The results of the
suspension equilibration experiments of solid form A and B' are
presented in Table 3.
TABLE-US-00006 TABLE 3 Start- Concen- ing tration Form form Solvent
mg/ml Conditions produced A n-heptane 108/2.0 23.degree. C.
(suspension) sonicated 5 min. (suspension) stirred 17 A
h/37.degree. C. (see FIG. 10a) filtered & air dried A n-heptane
+ 5% 117/2.1 23.degree. C. (suspension) ethanol v/v sonicated 5
min. (suspension) stirred 18 A h/37.degree. C. filtered & air
dried B' ethyl acetate + n- 81/1.7 23.degree. C. (suspension)
heptane 1:2 v/v stirred 2 A h/23.degree. C. (see FIG. 10b) filtered
& air dried A ethyl acetate + n- 124/2.0 23.degree. C.
(suspension) heptane 1:2 v/v stirred 3 A days/23.degree. C.
filtered & air dried A ethyl acetate + n- 126/2.0 +2.degree. C.
(suspension) heptane 1:2 v/v stirred 3 A days/+2.degree. C.
filtered & air dried B' ethyl acetate + n- 101/1.0 23.degree.
C. (suspension) pentane 1:2 v/v stirred 22 A h/23.degree. C. (see
FIG. 13c) filtered & air dried A ethyl acetate + n- 128/2.0
23.degree. C. (suspension) pentane 1:2 v/v stirred 20 A
h/23.degree. C. (see FIG. 10d) filtered & air dried A ethyl
formate + n- 112/2.0 23.degree. C. (suspension) pentane 1:2 v/v
stirred 20 A h/23.degree. C. (see FIG. 10e) filtered & air
dried A methyl acetate + n- 126/2.0 23.degree. C. (suspension)
pentane 1:2 v/v stirred 20 A h/23.degree. C. (see FIG. 10f)
filtered & air dried
Vapor Diffusion Experiments
Vapor diffusion experiments were carried out with solution of the
compound in different solvents. The solutions were placed in small,
open containers that were stored in larger vessels containing
miscible, volatile antisolvents. The larger vessels were then
tightly closed. The antisolvents diffused through the vapor phases
into the solutions, and saturation or supersaturation was achieved.
The results of the vapor diffusion experiments of solid form A and
B' are presented in Table 4.
TABLE-US-00007 TABLE 4 Concen- Anti- tration Form Solvent solvent
mg/ml Conditions produced ethanol n-hexane 204 mg P1 vapor
diffusion, viscous sticky 0.4 ml 23.degree. C., mass solvent 7
days, removed solution acetone n-hexane 210 mg P1 vapor diffusion,
viscous sticky 0.5 ml 23.degree. C., mass solvent 7 days, removed
solution TBME n-hexane 205 mg P1 vapor diffusion, viscous sticky
0.6 ml 23.degree. C., mass solvent 7 day, removed solution ethyl
acetate n-hexane 206 mg P1 vapor diffusion, very similar 0.6 ml
23.degree. C., 2 days, to A solvent filtered and air-dried THF
n-hexane 212 mg P1 vapor diffusion, viscous sticky 0.6 ml
23.degree. C., mass solvent 7 days, removed solution toluene
n-hexane 44 mg P1 vapor diffusion, very similar 2.0 ml 23.degree.
C., to A solvent 2 days, removed (see FIG. 11A) solution dichloro-
n-hexane 204 mg P1 vapor diffusion, very similar methane 1.6 ml
23.degree. C., to A solvent 2 days, removed solution 1,4-dioxane
n-hexane 215 mg P1 vapor diffusion, viscous sticky 0.5 ml
23.degree. C., mass solvent 7 days, removed solution acetic acid
water 219 mg P1 vapor diffusion, very similar 0.3 ml 23.degree. C.,
to A solvent 7 days, removed (see FIG. 11B) solution acetonitrile
water 212 mg P1 vapor diffusion, viscous sticky 0.4 ml 23.degree.
C., mass solvent 6 days, removed solution
Evaporation Experiments
Solutions of the compound were dried at room temperature (dry
nitrogen flow) without stirring. The results of the evaporation
experiments of solid form A are presented in Table 5.
TABLE-US-00008 TABLE 5 Start- Concen- ing tration Form form Solvent
mg/ml Conditions produced A ethanol 100/2.0 23.degree. C.
(solution) evaporated(dry N2) 2 B'' days/23.degree. C. A ethyl
109/2.0 23.degree. C. (solution) acetate evaporated (dry N.sub.2) 1
very similar day/23.degree. C. to A (see FIG. 12A) A THF 183/2.0
23.degree. C. (solution) evaporated (dry N.sub.2) 5 A + C
days/23.degree. C. (see FIG. 12B)
Precipitation Experiments
Precipitation experiments were carried out with 42-79 mg of the
compound. The to non-solvent was added to the solution. The samples
obtained after filtration (glass filter porosity P4) were air dried
at ambient temperature and for a short time only to prevent
possible desolvation of labile hydrates or solvates. The results of
the precipitation experiments of solid form A are presented in
Table 6.
TABLE-US-00009 TABLE 6 Start- Concen- ing tration Form form Solvent
mg/ml Conditions produced A ethanol 79/0.2 23.degree. C. (solution)
79/1.2 added of 1.0 ml n- (phase heptane separation) stored 11
weeks/-20.degree. C.; very similar removed solution to A and dried
solid residue (N.sub.2 43 ml/min) 50 min R.T. A ethyl 42/0.2
23.degree. C. (solution) acetate 42/1.2 added of 1.0 ml n- (viscous
sticky heptane mass) stirred 14 h/40.degree. C. A filtered &
air dried A THF 62/0.2 23.degree. C. (solution) 62/1.2 added of 1.0
ml n- (viscous sticky heptane mass) stirred 14 h/40.degree. C. A
filtered & air dried A dichloro- 75/0.3 23.degree. C.
(solution) methane 75/1.2 added of 1.0 ml n- (viscous sticky
heptane mass) stirred totally 13 h/ A 40.degree. C. filtered &
air dried
Recrystallization from Solution
The compound was dissolved in different solvent systems at room
temperature and cooled to +5.degree. C. or to -20.degree. C. The
samples obtained after filtration (glass filter porosity P4) were
air dried at ambient temperature for a short time only to prevent
possible desolvation of labile hydrates or solvates.
The results of the recrystallization experiments of solid form A
are presented in Table 7.
TABLE-US-00010 TABLE 7 Start- Concen- ing tration Form form Solvent
mg/ml Conditions produced A ethanol + 72/0.4 23.degree. C.
(solution) n-heptane stored 4 weeks/+5.degree. C.; A 1:1 v/v
filtration, washed (n- heptane) and air-dried A ethyl 80/1.2
23.degree. C. (solution) acetate + stored 4 weeks/-20.degree. C.;
very similar n-heptane filtered and air-dried to A 1:1 v/v (see
FIG. 13A) A acetonitrile + 91/0.2 23.degree. C. (solution) toluene
stored 4 weeks/-20.degree. C.; very similar 1:1 v/v removed
solution and to A dried solid residue (N.sub.2 43 ml/min) 212 min
R.T. A ethanol+ 52/0.4 23.degree. C. (solution) n-heptane stored 1
day/+5.degree. C.; A 1:3 v/v filtered, washd (n- heptane) and
air-dried A acetonitrile + 65/0.4 23.degree. C. (solution) toluene
stored 4 weeks/-20.degree. C.; very similar 1:3 v/v filtered and
air-dried to A (see FIG. 16B)
Freeze Drying Experiment
The compound was dissolved in 1,4-dioxane and the solution was
cooled to -50.degree. C. During sublimation of the solvent the
temperature of the solid was <0.degree. C. as presented in Table
8:
TABLE-US-00011 TABLE 8 Start- Concen- ing tration Form form Solvent
mg/ml Conditions produced A 1,4-dioxane 102/2.0 23.degree. C.
(solution) PP148-P1 freeze dried <0.degree. C. viscous sticky
mass stored 12 days/R.T. very similar to A (see FIG. 14)
Drying Experiment
The sample was dried overnight in a dry N.sub.2-atmosphere at room
temperature before closing the DSC sample pan.
The results are summarized in Table 9:
TABLE-US-00012 TABLE 9 Starting form mg Conditions DSC B' 3.6 mg
dried overnight 23.degree. C. FIG. 15 (mass loss 1.0%)
Cooling and Reheating of the Melt Experiments
After heating in DSC to 120.degree. C. the samples were cooled to
-50.degree. C. and reheated to 120.degree. C. The results are
summarized in Table 10:
TABLE-US-00013 TABLE 10 Starting form mg Conditions DSC A 3.4 mg
fast cooled to -50.degree. C., FIG. 7A heated: -50.degree. C. to
120.degree. C./20 K/min, fast cooled to -50.degree. C. heated
again: -50.degree. C. to 120.degree. C./20 K/min A 4.4 mg fast
cooled to -50.degree. C. FIG. 7B PP148-P2 heated: -50.degree. C. to
120.degree. C./20 K/min fast cooled to to -50.degree. C. C. heated
again: -50.degree. C. to 120.degree. C./20 K/min A 3.4 mg fast
cooled to -50.degree. C. FIG. 7C heated: -50.degree. C. to
120.degree. C./20 K/min fast cooled to -50.degree. C. C. heated
again: -50.degree. C. to 120.degree. C./20 K/min B' 2.9 mg fast
cooled to -50.degree. C. FIG. 7D heated: -50.degree. C. to
120.degree. C./20 K/min fast cooled to -50.degree. C. heated again:
-50.degree. C. to 120.degree. C./20 K/min
Relative Stability Experiments
Suspension experiments were carried out with 130-145 mg of the
compound. The suspensions were stirred with a magnetic stirrer and
filtered after a predefined time. The samples obtained after
filtration (glass filter porosity P4) were air dried at ambient
temperature. The results are summarized in Table 11:
TABLE-US-00014 TABLE 11 Start- Concen- ing tration Form forms
Solvent mg/ml Conditions produced A ethyl approx. 23.degree. C.
(suspension) acetate/n- 130/2.0 stirred 3 days/ A heptane
23.degree. C.; (see FIG. 16A) 1:2 (v/v) filtered and air-dried A
ethyl (81 + 64)/2.0 23.degree. C. (suspension) acetate/n- stirred 1
day/ A heptane 23.degree. C.; (see FIG. 16B) 1:2 (v/v) filtered and
air-dried
Water Solubility of Solid Forms A and B'
Suspensions of the solid forms (25 or 50 mg in 3.5 or 7.0 ml
bidistilled water) were shaken (800 rpm) and filtered after 0.5 h,
1.5 h, 4 h and 20 h. After filtration the solid residue was checked
by Raman spectroscopy and the concentration in the clear solution
was determined by HPLC.
The solubility of solid form A of S-1 in water at 22.degree. C. is
summarized in Table 12:
TABLE-US-00015 TABLE 12 Suspension equilibration Solubility.sup.a)
time [h] [mg/1000 ml] Solid residue.sup.b) 0.5 21.0 .+-. 3.9 A + B'
(approx. 95% + 5%).sup.c) 1.5 24.0 .+-. 1.4 A + B' (approx. 90% +
10%).sup.c) 4.0 27.6 .+-. 1.5 A + B' (approx. 85% + 15%).sup.c) 20
.sup. 24.5 .+-. 1.7.sup.d) A + B' (approx. 75% + 25%).sup.c)
.sup.a)Mean value of two measurements (.+-.standard deviation)
.sup.b)Raman measurements .sup.c)Rough estimate .sup.d)pH of the
solution: 8.7
The solubility of Form B' of S-1 in water at 22.degree. C. is
summarized in Table 13:
TABLE-US-00016 TABLE 13 Suspension equilibration Solubility .sup.a)
time [h] [mg/1000 ml] Solid residue .sup.b) 0.5 27.4 .+-. 0.9 B'
1.5 27.3 .+-. 0.8 B' 4.0 25.6 .+-. 0.1 B' 20 .sup. 26.7 .+-. 0.3
.sup.c) B' .sup.a) Mean value of two measurements (.+-.standard
deviation) .sup.b) Raman measurements .sup.c) Rough estimate
.sup.d) pH of the solution: 8.7
Characterization of S-1-P1 Form A
The starting material for the polymorphism study, batch no. S-1-P1,
is crystalline and the crystal form A. TG-FTIR shows that the mass
loss up to 200.degree. C. is very low (<0.2%) and therefore
batch no. S-1-P1 is not a hydrate or solvate. Batch no. S-1-P1
melts at 82.degree. C. (DSC peak temperature, heating rate 20K/min)
After melting and fast cooling to -50.degree. C. in DSC the
anhydrous liquid crystal form was produced. The sample showed a
phase transition temperature of approx. 52.degree. C. and did not
recrystallize during heating in DSC. S-1-P1 might contain a small
amount (roughly estimated 5%) of form B' or B''.
The DVS measurement of form A at 25.degree. C. does not show any
evidence of classical hydrate formation under the experimental
conditions used. The maximum water content at 93% relative
humidity. is 1.5%. The very slight hysteresis is most probably
caused by a viscous layer (possibly consisting of solid form B') on
the surface of the particles, which influences the rate of water
exchange. In fact, after storing form A at 96% relative humidity at
room temperature for 11 weeks, Raman spectroscopy and DSC indicated
the formation of approx. 20% of form B'.
Characterization of Solid Form B'
Investigations by DSC and XRPD indicate that the solid form
produced during storage of solid form A at 40.degree. C. and 75%
relative humidity. (batch S-1-P4; 40.degree. C./75% RH) is a
paracrystalline form, having limited low-range order. This limited
order most probably is responsible for the endothermal peak in DSC
around 55.degree. C. and the broad shoulder around 17.degree. in
the diffraction pattern. The solid form of batch S-1-P4 40.degree.
C./75% relative humidity is Form B'.
The DVS behavior of solid form B' at 25.degree. C. is not the
typical sorption behavior of a hydrate. The maximum water content
at 94% relative humidity. is approx. 2.4%. Even though a certain
hysteresis is observed, there is no clear step in the sorption
curve which would clearly indicate the existence of a classical
hydrate.
Formation of Solid Form B'
In addition to the observed transformation at high relative
humidity, solid form B' can be produced by stiffing a suspension of
solid form A in water at 37.degree. C. overnight.
Formation of Solid form B''
Pathways to produce solid form B'' are melting and cooling of the
melt, and slow evaporation of solutions in solvents such as
ethanol. Polymorph B'' can be prepared from polymorphs A and D by
heating them to above their respective melting points of 80.degree.
C. and 130.degree. C. B' and B'' are not distinguishable from any
analytical methods used thus far but are distinguished based on
their routes of formation. B' is assigned as a lyotropic liquid
crystalline form due to its solvent mediated formation while B'' is
assigned as a thermotropic liquid crystalline form from its thermal
method of preparation. Evaporation of the drug from solvents such
as ethanol without an antisolvent also produces B''.
Formation of Solid Form C
Polymorph C can only be obtained as a mixture with A by dissolving
and subsequently evaporating the drug out of THF at ambient
temperature.
Formation of Solid Form D
Polymorph D was originally produced by crystallization from a
solvent/antisolvent mixture at 50.degree. C. using ethyl acetate
and cyclohexane as the solvent and antisolvents respectively. Form
D can also be prepared from other polymorphic forms by "seeding"
the sample with a small amount of D and storing it at 110.degree.
C./0% RH for 7 days or at 50.degree. C. in water for 24 hours and
drying.
Formation of Solid Form Toluene Solvate
The toluene solvate was prepared by any solvent/antisolvent
crystallization method that used toluene as the antisolvent.
Water Solubility of Solid Forms A and B'
The solubility of forms A and B' of compound S-1 in water at
22.degree. C. are 24.0.+-.1.4 mg/1000 ml and 27.3.+-.0.8 mg/1000
ml, values obtained after 1.5 h suspension equilibration time.
These solubilities are very similar because of the fast
transformation of form A into form B' on the surface of the
particles during the solubility experiments.
Characterization of Different Batches of Solid Form A
Samples of batches S-1-P1, S-1-P2 and S-1-P3 show the same
diffraction pattern. to DSC measurements show that they most
probably contain several % of solid form B' or B'', indicated by
heat capacity changes around 50.degree. C. Sample S-1-P2 shows the
highest level of solid form B' or B'' (approx 20%). To better
understand the DSC results, scanning electron micrographs (SEM) of
samples S-1-P1 and S-1-P2 were produced. Whereas the pictures of
sample S-1-P1 show quite well-formed particles, the pictures of
sample S-1-P2 show a partial transformation, possibly caused by too
high a drying temperature or partial contact with water. The
partial formation of solid form B' or B'' could also be caused by
fast precipitation and a relatively high antisolvent/solvent ratio
after precipitation. Other explanations would be drying at high
temperatures or storage under high humidity conditions.
Solvent Systems for Crystallization of Solid Form A
Crystal form A is highly soluble in a number of solvents commonly
used for crystallization. Due to its high solubility,
solvent/antisolvent mixtures are necessary for crystallization.
Suspension equilibration experiments at room temperature revealed
that solid form B' (batch S-1-P4; 40.degree. C./75% RH) can be
transformed into solid form A when stirring suspensions in
ethylacetate/heptane 1:2 v/v or ethylacetate/pentane 1:2. In
addition, suspension equilibration experiments using solid form A
in ethyl formate/pentane 1:2 v/v and methyl acetate/pentane 1:2 v/v
showed no transformation of solid form A. Therefore, these class 3
solvent/antisolvent mixtures can be used for crystallization of
form A. The advantages of these solvent systems are the
significantly lower boiling temperatures and therefore the possibly
lower drying temperatures.
The details of the characterization of S-1-P1, solid Form A are
given in Table 14:
TABLE-US-00017 TABLE 14 Compound S-1 Batch no. S-1-P1 XRPD solid
form A FIGS. XRPD-1a and XRPD-1b (see FIG. 4A) Raman solid form A
FIG. Raman-1 (see sample might contain a small FIG. 5A) amount of
B' or B'' TG-FTIR mass loss 25.degree. C. to 245.degree. FIG.
TG-FTIR-1 C.: <0.2% (see FIG. 6A) DSC melting temperature:
82.4.degree. C. FIGS. DSC-1a and (peak temperature, hermetically
DSC-1b (See FIG. sealed gold sample pan, 7A) heating rate 20 K/min)
AH: -42 J/g sample might contain a small amount (roughly estimated
5%) of form B' or B'' SEM quite well-formed particles FIGS. SEM-1
(see FIG. 8A DVS water content at 50% r.h.: 0.4% FIGS. DVS-1a and
maximum water content at 93% DVS-1b (FIG. 9A r.h.: 1.5%
The details of the characterization of S-1-P2, solid Form A, are
given in Table 15:
TABLE-US-00018 TABLE 15 Compound S-1 Batch no. S-1-P2 XRPD solid
form A FIGS. XRPD-2a and XRPD-2b (see FIG. 4B) Raman solid form A +
B' or B'' FIG. Raman-2 (See FIG. 5B) TG-FTIR mass loss 25.degree.
C. to 245.degree. FIG. TG-FTIR-2 C.: <0.2% (see FIG. 6B) DSC
melting temperature: 85.4.degree. C. FIGS. DSC-2a and (peak
temperature, hermetically DSC-2b (see FIG. sealed gold sample pan,
7B) heating rate 20 K/min) AH: -43 J/g sample contains approx. 20%
of form B' or B'' SEM pictures show partial FIGS. SEM-2 (see
transformation FIG. 8B) DVS water content at 50% r.h.: 0.3% FIGS.
DVS-2a and maximum water content at 95% DVS-2b (see FIG. r.h.: 0.6%
9B)
The details of the characterization of S-1-P3, solid Form A, are
given in Table 16:
TABLE-US-00019 TABLE 16 Compound S-1 Batch no. S-1-P3 XRPD solid
form A FIGS. XRPD-3a and XRPD-3b (see FIG. 4C) Raman solid form A
FIG. Raman-3 (see sample might contain a small FIG. 5C) amount of
B' or B'' TG-FTIR mass loss 25.degree. C. to 245.degree. FIG.
TG-FTIR-3 C.: <0.2% (see FIG. 6C DSC melting temperature:
84.4.degree. C. FIGS. DSC-3a and (peak temperature, hermetically
DSC-3b (see FIG. sealed gold sample pan, 7C heating rate 20 K/min)
AH: -42 J/g sample might contain a small amount (roughly estimated
5%) of form B' or B'' SEM not analyzed -- DVS not analyzed --
The details of the characterization of S-1-P4, solid Form B' are
given in Table 17:
TABLE-US-00020 TABLE 17 Compound S-1 Batch no. S-1-P4 40.degree.
C./75% RH XRPD solid form B' FIGS. XRPD-4a sample might contain a
small and XRPD-4b (see amount of form A FIG. 4D) Raman solid form
B' FIG. Raman-4 (see FIG. 5D) TG-FTIR mass loss 25.degree. C. to
245.degree. FIG. TG-FTIR-4 C.: 1.0% (water) (see FIG. 6D) DSC
endothermal peak: ~55.degree. C. FIGS. DSC-4a and (peak
temperature, hermetically DSC-4b (see FIG. sealed gold sample pan,
heating 7D) rate 20 K/min) AH: ~10 J/g SEM significant change in
morphology FIGS. SEM-3 (see FIG. 8C) DVS water content at 50% r.h.:
~0.8% FIGS. DVS-3a and maximum water content at 94% DVS-3b (see
FIG. r.h.: ~2.4% 9C)
The different batches P1, P2 and P3 of compound S-1 revealed
crystalline Form A with similar characteristic behavior of XRPD,
Raman, TG FTIR, DVS and DSC results. Batch P4 revealed a
paracrystalline solid form as characterized by its broad XRPD,
Raman, TG FTIR, DVS and DSC results as described hereinabove.
Relative Stability of Polymorphic Forms Under Dry Conditions
The DSC thermogram of A and D in FIG. 19 show that A melts near
80.degree. C. while D has a melting point near 130.degree. C. The
enthalpy of melting for A is 40.+-.5 J/g while the enthalpy of
melting is 75.+-.5 J/g. The melting temperature and enthalpy
suggest that D possesses greater stability in comparison to form
A.
FIG. 17D shows that melting of polymorphs A or D produces the
liquid crystalline B'' polymorph instead of a truly isotropic
liquid phase. Formation of a true liquid phase was not observed
even after heating the sample to 200.degree. C. Cooling the B''
polymorph to ambient temperature does not result in
recrystallization back to form A or D. This is verified by the
absence of a melting endotherm in the DSC curve (FIG. 17D) of the
sample reheated after it was melted then subsequently cooled to
ambient temperature. The DSC curve also shows that the B'' form
undergoes a phase transition near 55.degree. C. Similar glass
transitions are observed for B', which along with the broad
shoulder around 17.degree. in FIG. 4D are the basis for their
designation as liquid crystalline phases. The XRPD displays
harmonic peaks for B', along with the broad shoulder around
17.degree. in FIG. 4D which are the basis for their designation as
liquid crystalline phases.
FIG. 17e shows that heating of polymorphs A and B'' to 110.degree.
C. in the presence of D causes the A and B'' forms to rearrange
into D. This confirms that the A and B'' are metastable phases
below 130.degree. C. that can be converted to form D. However,
likely due to the high energetic barrier for the transition, the
rates of conversion of A or B'' to D are very slow without any D
present initially to seed the crystallization. Thus forms A and B''
can be considered to be practically stable at ambient temperature.
Above 130.degree. C., form D melts and changes to B'' which now
becomes the most stable form. Micronization of the polymorph A
particles under dry conditions also produced--25% conversion to
B''.
Relative Stability of Polymorphic Forms Under Humid Conditions
Polymorph A stays stable in its A form for at least 7 days under
storage conditions of ambient temperature/75% RH (Relative
Humidity), ambient temperature/100% RH, 30.degree. C./75% RH and
50.degree. C./0% RH. But it converts to B' when stored at
50.degree. C./75% RH. Some of the results are shown in FIG. 17F. In
fact, polymorph A stored at 25.degree. C./60% RH and 30.degree.
C./65% RH were stable through 36 months and 9 months respectively
while a sample stored at 40.degree. C./75% RH converted to B'
within one month. These results indicate that polymorph A converts
to B' in the presence of moisture.
Polymorph D on the other hand, remains stable at 50.degree. C./75%
RH as well as the other conditions of ambient/75% RH, ambient/100%
RH, 30.degree. C./75% RH and 50.degree. C./0% RH. In fact,
polymorph D in the presence of moisture acts as the seed for the
crystallization process and drives the transformation of polymorphs
A and B' into D, similar to its role in seeding the A to D
crystallization in dry conditions. FIG. 17G(a) shows the time
evolution of polymorph A seeded with a small amount of D at
50.degree. C./75% RH. The amount of polymorph D initially added to
the sample is very small that it isn't detectable by the DSC with
heating rate of 10.degree. C./min. After 24 hours, most of the
polymorph form A has been converted to B' but a small amount of
sample has also been converted to D and the amount of sample in D
increases over time. The transformation process is speeded up in
FIG. 17G(b) by storing the sample in water at 50.degree. C. Form A
has been converted to both B' and D after 6 hours but the sample is
predominantly in form D by 24 hours. This is in contrast to the
conversion to B' of the pure A form which doesn't convert further
to D. It is yet unclear if A can convert to D directly with seeding
in water or if it only converts to B' (which subsequently converts
to D in water). Further work has shown that the A and B' convert to
D in the presence of moisture at lower temperatures also albeit at
slower rates.
Relative Stability of Toluene Solvate in Toluene
Recrystallization of S-1 from a solvent/antisolvent system that
uses toluene as the antisolvent produces the toluene solvate.
Toluene solvate has a melting point near 100.degree. C. with the
enthalpy of melting 70.+-.5 J/g. TGA graph of the toluene solvate
in FIG. 20 shows that the toluene content in the solvate is
.about.7% which corresponds to one toluene molecule for every three
molecules of S-1. The solvent/drug mass ratio stayed the same for
each sample batch prepared and suggests that the toluene molecules
reside inside the unit cell structure rather than in channels or
layers outside the lattice. Owing to the low solubility of S-1 in
toluene (<2 mg/mL), no noticeable transformation from form D to
the toluene solvate was observed after suspension (50 mg/mL) in
toluene for 4 days both at ambient temperature and 50.degree. C.
Sonication of the suspension for 10 minutes did produce partial
transformation to the toluene solvate.
It will be appreciated by a person skilled in the art that the
present invention is not limited by what has been particularly
shown and described hereinabove. Rather, the scope of the invention
is defined by the claims that follow:
* * * * *